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Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates

Nature Reviews Immunology volume 13, pages 206–218 (2013)Cite this article

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Abstract

Complex barriers separate immune-privileged tissues from the circulation. Here, we propose that cell entry to immune-privileged sites through barriers composed of tight junction-interconnected endothelium is associated with destructive inflammation, whereas border structures comprised of fenestrated vasculature enveloped by tightly regulated epithelium serve as active and selective immune-skewing gates in the steady state. Based on emerging knowledge of the central nervous system and information from other immune-privileged sites, we propose that these sites are endowed either with absolute endothelial-based barriers and epithelial gates that enable selective and educative transfer of trafficking leukocytes or with selective epithelial gates only.

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Figure 1: The CNS gating system.
Figure 2: The ocular gating system.
Figure 3: The maternal–fetal interface gating system.
Figure 4: The testis gating system.

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References

  1. Ley, K., Laudanna, C., Cybulsky, M. I. & Nourshargh, S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Rev. Immunol. 7, 678–689 (2007).

    Article  CAS  Google Scholar 

  2. Huber, D., Balda, M. S. & Matter, K. Occludin modulates transepithelial migration of neutrophils. J. Biol. Chem. 275, 5773–5778 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Ransohoff, R. M. & Engelhardt, B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nature Rev. Immunol. 12, 623–635 (2012).

    Article  CAS  Google Scholar 

  4. Streilein, J. W. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nature Rev. Immunol. 3, 879–889 (2003).

    Article  CAS  Google Scholar 

  5. Naito, M. et al. The presence of intra-tubular lymphocytes in normal testis of the mouse. Okajimas Folia Anat. Jpn 85, 91–96 (2008).

    Article  PubMed  Google Scholar 

  6. Goyal, H. O. & Williams, C. S. The rete testis of the goat, a morphological study. Acta Anat. (Basel) 130, 151–157 (1987).

    Article  CAS  Google Scholar 

  7. Nelson, J. L. The otherness of self: microchimerism in health and disease. Trends Immunol. 33, 421–427 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Takashima, S. et al. Rac mediates mouse spermatogonial stem cell homing to germline niches by regulating transmigration through the blood-testis barrier. Cell Stem Cell 9, 463–475 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Wang, C. Q. & Cheng, C. Y. A seamless trespass: germ cell migration across the seminiferous epithelium during spermatogenesis. J. Cell Biol. 178, 549–556 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Engelhardt, B. & Ransohoff, R. M. Capture, crawl, cross: the T cell code to breach the blood-brain barriers. Trends Immunol. 33, 579–589 (2012).

    Article  CAS  PubMed  Google Scholar 

  11. Alvarez, J. I. et al. The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence. Science 334, 1727–1731 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Sonobe, Y. et al. Interleukin-25 expressed by brain capillary endothelial cells maintains blood-brain barrier function in a protein kinase Cɛ-dependent manner. J. Biol. Chem. 284, 31834–31842 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cruz-Orengo, L. et al. CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity. J. Exp. Med. 208, 327–339 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. McCandless, E. E., Wang, Q., Woerner, B. M., Harper, J. M. & Klein, R. S. CXCL12 limits inflammation by localizing mononuclear infiltrates to the perivascular space during experimental autoimmune encephalomyelitis. J. Immunol. 177, 8053–8064 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Alt, C., Laschinger, M. & Engelhardt, B. Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis. Eur. J. Immunol. 32, 2133–2144 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Galea, I. et al. An antigen-specific pathway for CD8 T cells across the blood-brain barrier. J. Exp. Med. 204, 2023–2030 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nature Med. 11, 328–334 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Ifergan, I. et al. The blood-brain barrier induces differentiation of migrating monocytes into Th17- polarizing dendritic cells. Brain 131, 785–799 (2008).

    Article  PubMed  Google Scholar 

  19. Seguin, R., Biernacki, K., Rotondo, R. L., Prat, A. & Antel, J. P. Regulation and functional effects of monocyte migration across human brain-derived endothelial cells. J. Neuropathol. Exp. Neurol. 62, 412–419 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Agrawal, S. et al. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J. Exp. Med. 203, 1007–1019 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shechter, R. et al. Recruitment of beneficial M2 macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity (in the press).

  22. Provencio, J. J., Kivisakk, P., Tucky, B. H., Luciano, M. G. & Ransohoff, R. M. Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients. J. Neuroimmunol. 163, 179–184 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Baruch, K. et al. CNS-specific immunity at the choroid plexus shifts towards destructive Th2-inflammation in brain aging. Proc. Natl Acad. Sci. USA 18 Jan 2013 (doi:10.1073/pnas.1211270110).

  24. Kivisakk, P. et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc. Natl Acad. Sci. USA 100, 8389–8394 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Buonamici, S. et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature 459, 1000–1004 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Taylor, A. W. & Streilein, J. W. Inhibition of antigen-stimulated effector T cells by human cerebrospinal fluid. Neuroimmunomodulation 3, 112–118 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Trabold, B., Rothoerl, R., Wittmann, S., Woertgen, C. & Frohlich, D. Cerebrospinal fluid and neutrophil respiratory burst after subarachnoid hemorrhage. Neuroimmunomodulation 12, 152–156 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Gordon, L. B., Nolan, S. C., Ksander, B. R., Knopf, P. M. & Harling-Berg, C. J. Normal cerebrospinal fluid suppresses the in vitro development of cytotoxic T cells: role of the brain microenvironment in CNS immune regulation. J. Neuroimmunol. 88, 77–84 (1998).

    Article  CAS  PubMed  Google Scholar 

  29. De Rotte, A. A., Verhoef, J., Andringa-Bakker, E. A. & Van Wimersma Greidanus, T. B. Characterization of the α-MSH-like immunoreactivity in blood and cerebrospinal fluid of the rat. Acta Endocrinol. 111, 440–444 (1986).

    Article  CAS  Google Scholar 

  30. Suzuki, H. et al. Pituitary protein 7B2-like immunoreactivity in cerebrospinal fluid: comparison with other neuropeptides. J. Lab. Clin. Med. 113, 743–748 (1989).

    CAS  PubMed  Google Scholar 

  31. Pentreath, V. W., Rees, K., Owolabi, O. A., Philip, K. A. & Doua, F. The somnogenic T lymphocyte suppressor prostaglandin D2 is selectively elevated in cerebrospinal fluid of advanced sleeping sickness patients. Trans. R. Soc. Trop. Med. Hyg. 84, 795–799 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. Tarkowski, E., Liljeroth, A. M., Nilsson, A., Minthon, L. & Blennow, K. Decreased levels of intrathecal interleukin 1 receptor antagonist in Alzheimer's disease. Dement. Geriatr. Cogn. Disord. 12, 314–317 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Haginoya, K. et al. Reduced levels of interleukin-1 receptor antagonist in the cerebrospinal fluid in patients with West syndrome. Epilepsy Res. 85, 314–317 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Mueller, A. M., Pedre, X., Killian, S., David, M. & Steinbrecher, A. The Decoy Receptor 3 (DcR3, TNFRSF6B) suppresses Th17 immune responses and is abundant in human cerebrospinal fluid. J. Neuroimmunol. 209, 57–64 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Pan, Y. et al. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 387, 611–617 (1997).

    Article  CAS  PubMed  Google Scholar 

  36. Mills, J. H. et al. CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105, 9325–9330 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mills, J. H., Kim, D. G., Krenz, A., Chen, J. F. & Bynoe, M. S. A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis. J. Immunol. 188, 5713–5722 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Fujiwara, M. et al. Indoleamine 2,3-dioxygenase. Formation of L-kynurenine from L-tryptophan in cultured rabbit fineal gland. J. Biol. Chem. 253, 6081–6085 (1978).

    CAS  PubMed  Google Scholar 

  40. Yamamoto, M., Drager, U. C., Ong, D. E. & McCaffery, P. Retinoid-binding proteins in the cerebellum and choroid plexus and their relationship to regionalized retinoic acid synthesis and degradation. Eur. J. Biochem. 257, 344–350 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nature Immunol. 10, 514–523 (2009).

    Article  CAS  Google Scholar 

  42. Kleinewietfeld, M. et al. CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset. Blood 105, 2877–2886 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Schulz, M. & Engelhardt, B. The circumventricular organs participate in the immunopathogenesis of experimental autoimmune encephalomyelitis. Cerebrospinal Fluid Res. 266, 8 (2005).

    Article  CAS  Google Scholar 

  44. Schmitt, C., Strazielle, N. & Ghersi-Egea, J. F. Brain leukocyte infiltration initiated by peripheral inflammation or experimental autoimmune encephalomyelitis occurs through pathways connected to the CSF-filled compartments of the forebrain and midbrain. J. Neuroinflamm. 966, 187 (2012).

    Google Scholar 

  45. Alvarez, J. I. & Teale, J. M. Differential changes in junctional complex proteins suggest the ependymal lining as the main source of leukocyte infiltration into ventricles in murine neurocysticercosis. J. Neuroimmunol. 187, 102–113 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Burton, A. R. et al. Central nervous system destruction mediated by glutamic acid decarboxylase-specific CD4+ T cells. J. Immunol. 184, 4863–4870 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Marvar, P. J. et al. Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension. Circ. Res. 107, 263–270 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Carrithers, M. D., Visintin, I., Kang, S. J. & Janeway, C. A. Jr. Differential adhesion molecule requirements for immune surveillance and inflammatory recruitment. Brain 123, 1092–1101 (2000).

    Article  PubMed  Google Scholar 

  49. Piccio, L. et al. Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric Gi-linked receptors. J. Immunol. 168, 1940–1949 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Derecki, N. C. et al. Regulation of learning and memory by meningeal immunity: a key role for IL-4. J. Exp. Med. 207, 1067–1080 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kim, J. V., Kang, S. S., Dustin, M. L. & McGavern, D. B. Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457, 191–195 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Bartholomaus, I. et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462, 94–98 (2009).

    Article  PubMed  Google Scholar 

  53. Ajami, B., Bennett, J. L., Krieger, C., McNagny, K. M. & Rossi, F. M. Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nature Neurosci. 14, 1142–1149 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Kivisakk, P. et al. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann. Neurol. 65, 457–469 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wieseler-Frank, J. et al. A novel immune-to-CNS communication pathway: cells of the meninges surrounding the spinal cord CSF space produce proinflammatory cytokines in response to an inflammatory stimulus. Brain Behav. Immun. 21, 711–718 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Kaur, C., Foulds, W. S. & Ling, E. A. Blood-retinal barrier in hypoxic ischaemic conditions: basic concepts, clinical features and management. Prog. Retin. Eye Res. 27, 622–647 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Luna, J. D. et al. Blood-retinal barrier (BRB) breakdown in experimental autoimmune uveoretinitis: comparison with vascular endothelial growth factor, tumor necrosis factor α, and interleukin-1β-mediated breakdown. J. Neurosci. Res. 49, 268–280 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Kerr, E. C., Copland, D. A., Dick, A. D. & Nicholson, L. B. The dynamics of leukocyte infiltration in experimental autoimmune uveoretinitis. Prog. Retin. Eye Res. 27, 527–535 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Luger, D. et al. Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J. Exp. Med. 205, 799–810 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Parnaby-Price, A. et al. Leukocyte trafficking in experimental autoimmune uveitis in vivo. J. Leukoc. Biol. 64, 434–440 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Joly, S. et al. Cooperative phagocytes: resident microglia and bone marrow immigrants remove dead photoreceptors in retinal lesions. Am. J. Pathol. 174, 2310–2323 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sugita, S., Futagami, Y., Smith, S. B., Naggar, H. & Mochizuki, M. Retinal and ciliary body pigment epithelium suppress activation of T lymphocytes via transforming growth factor β. Exp. Eye Res. 83, 1459–1471 (2006).

    Article  CAS  PubMed  Google Scholar 

  63. Sugita, S. Role of ocular pigment epithelial cells in immune privilege. Arch. Immunol. Ther. Exp. (Warsz) 57, 263–268 (2009).

    Article  Google Scholar 

  64. Fang, Y., Yu, S., Ellis, J. S., Sharav, T. & Braley-Mullen, H. Comparison of sensitivity of Th1, Th2, and Th17 cells to Fas-mediated apoptosis. J. Leukoc. Biol. 87, 1019–1028 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ishida, K., Panjwani, N., Cao, Z. & Streilein, J. W. Participation of pigment epithelium in ocular immune privilege. 3. Epithelia cultured from iris, ciliary body, and retina suppress T-cell activation by partially non-overlapping mechanisms. Ocul. Immunol. Inflamm. 11, 91–105 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Gregerson, D. S., Heuss, N. D., Lew, K. L., McPherson, S. W. & Ferrington, D. A. Interaction of retinal pigmented epithelial cells and CD4 T cells leads to T-cell anergy. Invest. Ophthalmol. Vis. Sci. 48, 4654–4663 (2007).

    Article  PubMed  Google Scholar 

  67. Prendergast, R. A. et al. T cell traffic and the inflammatory response in experimental autoimmune uveoretinitis. Invest. Ophthalmol. Vis. Sci. 39, 754–762 (1998).

    CAS  PubMed  Google Scholar 

  68. Sugita, S. & Streilein, J. W. Iris pigment epithelium expressing CD86 (B7-2) directly suppresses T cell activation in vitro via binding to cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 198, 161–171 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sugita, S., Ng, T. F., Schwartzkopff, J. & Streilein, J. W. CTLA-4+CD8+ T cells that encounter B7-2+ iris pigment epithelial cells express their own B7-2 to achieve global suppression of T cell activation. J. Immunol. 172, 4184–4194 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Yoshida, M., Kezuka, T. & Streilein, J. W. Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. 2. Generation of TGF-β-producing regulatory T cells. Invest. Ophthalmol. Vis. Sci. 41, 3862–3870 (2000).

    CAS  PubMed  Google Scholar 

  71. Sugita, S. et al. B7+ iris pigment epithelial cells convert T cells into CTLA-4+, B7-expressing CD8+ regulatory T cells. Invest. Ophthalmol. Vis. Sci. 47, 5376–5384 (2006).

    Article  PubMed  Google Scholar 

  72. Yoshida, M., Takeuchi, M. & Streilein, J. W. Participation of pigment epithelium of iris and ciliary body in ocular immune privilege. 1. Inhibition of T-cell activation in vitro by direct cell-to-cell contact. Invest. Ophthalmol. Vis. Sci. 41, 811–821 (2000).

    CAS  PubMed  Google Scholar 

  73. Taylor, A. W., Alard, P., Yee, D. G. & Streilein, J. W. Aqueous humor induces transforming growth factor-β (TGF-β)-producing regulatory T-cells. Curr. Eye Res. 16, 900–908 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Taylor, A. W., Yee, D. G. & Streilein, J. W. Suppression of nitric oxide generated by inflammatory macrophages by calcitonin gene-related peptide in aqueous humor. Invest. Ophthalmol. Vis. Sci. 39, 1372–1378 (1998).

    CAS  PubMed  Google Scholar 

  75. Taylor, A. W., Streilein, J. W. & Cousins, S. W. Immunoreactive vasoactive intestinal peptide contributes to the immunosuppressive activity of normal aqueous humor. J. Immunol. 153, 1080–1086 (1994).

    CAS  PubMed  Google Scholar 

  76. D'Orazio, T. J., DeMarco, B. M., Mayhew, E. S. & Niederkorn, J. Y. Effect of aqueous humor on apoptosis of inflammatory cell types. Invest. Ophthalmol. Vis. Sci. 40, 1418–1426 (1999).

    CAS  PubMed  Google Scholar 

  77. Zhou, R., Horai, R., Mattapallil, M. J. & Caspi, R. R. A new look at immune privilege of the eye: dual role for the vision-related molecule retinoic acid. J. Immunol. 187, 4170–4177 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Mo, J. S. & Streilein, J. W. Immune privilege persists in eyes with extreme inflammation induced by intravitreal LPS. Eur. J. Immunol. 31, 3806–3815 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Ohta, K., Wiggert, B., Yamagami, S., Taylor, A. W. & Streilein, J. W. Analysis of immunomodulatory activities of aqueous humor from eyes of mice with experimental autoimmune uveitis. J. Immunol. 164, 1185–1192 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Ohta, K., Yamagami, S., Taylor, A. W. & Streilein, J. W. IL-6 antagonizes TGF-β and abolishes immune privilege in eyes with endotoxin-induced uveitis. Invest. Ophthalmol. Vis. Sci. 41, 2591–2599 (2000).

    CAS  PubMed  Google Scholar 

  81. Erlebacher, A. Mechanisms of T cell tolerance towards the allogeneic fetus. Nature Rev. Immunol. 13, 23–33 (2013).

    Article  CAS  Google Scholar 

  82. Moffett, A. & Loke, C. Immunology of placentation in eutherian mammals. Nature Rev. Immunol. 6, 584–594 (2006).

    Article  CAS  Google Scholar 

  83. Kovats, S. et al. A class I antigen, HLA-G, expressed in human trophoblasts. Science 248, 220–223 (1990).

    Article  CAS  PubMed  Google Scholar 

  84. Rouas-Freiss, N., Goncalves, R. M., Menier, C., Dausset, J. & Carosella, E. D. Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proc. Natl Acad. Sci. USA 94, 11520–11525 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Fournel, S. et al. Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. J. Immunol. 164, 6100–6104 (2000).

    Article  CAS  PubMed  Google Scholar 

  86. Carosella, E. D., Moreau, P., Aractingi, S. & Rouas-Freiss, N. HLA-G: a shield against inflammatory aggression. Trends Immunol. 22, 553–555 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Ristich, V., Liang, S., Zhang, W., Wu, J. & Horuzsko, A. Tolerization of dendritic cells by HLA-G. Eur. J. Immunol. 35, 1133–1142 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Chang, C. C. et al. Tolerization of dendritic cells by TS cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nature Immunol. 3, 237–243 (2002).

    Article  CAS  Google Scholar 

  89. Sacks, G. P., Clover, L. M., Bainbridge, D. R., Redman, C. W. & Sargent, I. L. Flow cytometric measurement of intracellular Th1 and Th2 cytokine production by human villous and extravillous cytotrophoblast. Placenta 22, 550–559 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Liu, F. et al. Placental trophoblasts shifted Th1/Th2 balance toward Th2 and inhibited Th17 immunity at fetomaternal interface. APMIS 119, 597–604 (2011).

    Article  CAS  PubMed  Google Scholar 

  91. Schumacher, A. et al. Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy. J. Immunol. 182, 5488–5497 (2009).

    Article  CAS  PubMed  Google Scholar 

  92. Siiteri, P. K. & Stites, D. P. Immunologic and endocrine interrelationships in pregnancy. Biol. Reprod. 26, 1–14 (1982).

    Article  CAS  PubMed  Google Scholar 

  93. Piccinni, M. P. et al. Progesterone favors the development of human T helper cells producing Th2-type cytokines and promotes both IL-4 production and membrane CD30 expression in established Th1 cell clones. J. Immunol. 155, 128–133 (1995).

    CAS  PubMed  Google Scholar 

  94. Zorzi, W. et al. Demonstration of the expression of CD95 ligand transcript and protein in human placenta. Placenta 19, 269–277 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Jerzak, M. & Bischof, P. Apoptosis in the first trimester human placenta: the role in maintaining immune privilege at the maternal-foetal interface and in the trophoblast remodelling. Eur. J. Obstet. Gynecol. Reprod. Biol. 100, 138–142 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Hsi, B. L., Hunt, J. S. & Atkinson, J. P. Differential expression of complement regulatory proteins on subpopulations of human trophoblast cells. J. Reprod. Immunol. 19, 209–223 (1991).

    Article  CAS  PubMed  Google Scholar 

  97. Petroff, M. G. et al. B7 family molecules are favorably positioned at the human maternal-fetal interface. Biol. Reprod. 68, 1496–1504 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Suzuki, K. & Tomasi, T. B. Jr. Mechanism of immune suppression by murine neonatal fluids. J. Immunol. 125, 1806–1810 (1980).

    CAS  PubMed  Google Scholar 

  99. Wilbanks, G. A. & Streilein, J. W. Fluids from immune privileged sites endow macrophages with the capacity to induce antigen-specific immune deviation via a mechanism involving transforming growth factor-β. Eur. J. Immunol. 22, 1031–1036 (1992).

    Article  CAS  PubMed  Google Scholar 

  100. Shohat, B. & Faktor, J. M. Immunosuppressive activity of human amniotic fluid of normal and abnormal pregnancies. Int. J. Fertil. 33, 273–277 (1988).

    CAS  PubMed  Google Scholar 

  101. Murgita, R. A. & Tomasi, T. B. Jr. Suppression of the immune response by α-fetoprotein on the primary and secondary antibody response. J. Exp. Med. 141, 269–286 (1975).

    Article  CAS  PubMed  Google Scholar 

  102. Pressman, E. K. et al. Inflammatory cytokines and antioxidants in midtrimester amniotic fluid: correlation with pregnancy outcome. Am J. Obstet Gynecol. 204, 155.e1–155.e7 (2011).

    Article  CAS  Google Scholar 

  103. Mital, P., Hinton, B. T. & Dufour, J. M. The blood-testis and blood-epididymis barriers are more than just their tight junctions. Biol. Reprod. 84, 851–858 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Fijak, M. & Meinhardt, A. The testis in immune privilege. Immunol. Rev. 213, 66–81 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. Mital, P., Kaur, G. & Dufour, J. M. Immunoprotective sertoli cells: making allogeneic and xenogeneic transplantation feasible. Reproduction 139, 495–504 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Suarez-Pinzon, W. et al. Testicular sertoli cells protect islet β-cells from autoimmune destruction in NOD mice by a transforming growth factor-β1-dependent mechanism. Diabetes 49, 1810–1818 (2000).

    Article  CAS  PubMed  Google Scholar 

  107. Sipione, S. et al. Identification of a novel human granzyme B inhibitor secreted by cultured sertoli cells. J. Immunol. 177, 5051–5058 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Liva, S. M. & Voskuhl, R. R. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J. Immunol. 167, 2060–2067 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Skinner, M. K. & Moses, H. L. Transforming growth factor β gene expression and action in the seminiferous tubule: peritubular cell-Sertoli cell interactions. Mol. Endocrinol. 3, 625–634 (1989).

    Article  CAS  PubMed  Google Scholar 

  110. Gerdprasert, O. et al. Expression of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor in normal and inflamed rat testis. Mol. Hum. Reprod. 8, 518–524 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Piquet-Pellorce, C., Dorval-Coiffec, I., Pham, M. D. & Jegou, B. Leukemia inhibitory factor expression and regulation within the testis. Endocrinology 141, 1136–1141 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Breucker, H. Macrophages, a normal component in seasonally involuting testes of the swan, Cygnus olor. Cell Tissue Res. 193, 463–471 (1978).

    Article  CAS  PubMed  Google Scholar 

  113. Naito, M. & Itoh, M. Patterns of infiltration of lymphocytes into the testis under normal and pathological conditions in mice. Am. J. Reprod. Immunol. 59, 55–61 (2008).

    Article  PubMed  Google Scholar 

  114. Naito, M. et al. Histopathology of the tubuli recti at the start of experimental autoimmune orchitis in mice. Med. Mol. Morphol. 42, 230–235 (2009).

    Article  PubMed  Google Scholar 

  115. Schmorl, C. in Pathologisch-anatomische Untersuchungen uber Puerperal-Eklampsie (Verlag von F.C.W. Vogel, 1893).

    Google Scholar 

  116. Reynolds, A. G. Placental metastasis from malignant melanoma; report of a case. Obstet. Gynecol. 6, 205–209 (1955).

    CAS  PubMed  Google Scholar 

  117. Schroder, J. & De la Chapelle, A. Fetal lymphocytes in the maternal blood. Blood 39, 153–162 (1972).

    CAS  PubMed  Google Scholar 

  118. Loubiere, L. S. et al. Maternal microchimerism in healthy adults in lymphocytes, monocyte/macrophages and NK cells. Lab Invest. 86, 1185–1192 (2006).

    Article  CAS  PubMed  Google Scholar 

  119. Khosrotehrani, K., Johnson, K. L., Cha, D. H., Salomon, R. N. & Bianchi, D. W. Transfer of fetal cells with multilineage potential to maternal tissue. JAMA 292, 75–80 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Srivatsa, B. Srivatsa, S., Johnson, K. L. & Bianchi, D. W. Maternal cell microchimerism in newborn tissues. J. Pediatr. 142, 31–35 (2003).

    Article  PubMed  Google Scholar 

  121. O'Donoghue, K. et al. Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 364, 179–182 (2004).

    Article  PubMed  Google Scholar 

  122. Evans, P. C. et al. Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma. Blood 93, 2033–2037 (1999).

    CAS  PubMed  Google Scholar 

  123. Nelson, J. L. et al. Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet β cell microchimerism. Proc. Natl Acad. Sci. USA 104, 1637–1642 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Maloney, S. et al. Microchimerism of maternal origin persists into adult life. J. Clin. Invest. 104, 41–47 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Isoda, T. et al. Immunologically silent cancer clone transmission from mother to offspring. Proc. Natl Acad. Sci. USA 106, 17882–17885 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Stevens, A. M., Hermes, H. M., Rutledge, J. C., Buyon, J. P. & Nelson, J. L. Myocardial-tissue-specific phenotype of maternal microchimerism in neonatal lupus congenital heart block. Lancet 362, 1617–1623 (2003).

    Article  PubMed  Google Scholar 

  127. Mold, J. E. et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322, 1562–1565 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nijagal, A. et al. Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice. J. Clin. Invest. 121, 582–592 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Burlingham, W. J. A lesson in tolerance--maternal instruction to fetal cells. N. Engl. J. Med. 360, 1355–1357 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chen, C. P. et al. Trafficking of multipotent mesenchymal stromal cells from maternal circulation through the placenta involves vascular endothelial growth factor receptor-1 and integrins. Stem Cells 26, 550–561 (2008).

    Article  CAS  PubMed  Google Scholar 

  131. Chadwick, V. S. et al. Production of peptides inducing chemotaxis and lysosomal enzyme release in human neutrophils by intestinal bacteria in vitro and in vivo. Scand. J. Gastroenterol. 23, 121–128 (1988).

    Article  CAS  PubMed  Google Scholar 

  132. Arques, J. L. et al. Salmonella induces flagellin- and MyD88-dependent migration of bacteria-capturing dendritic cells into the gut lumen. Gastroenterology 137, 579–587.e2 (2009).

    Article  PubMed  Google Scholar 

  133. Rescigno, M. The intestinal epithelial barrier in the control of homeostasis and immunity. Trends Immunol. 32, 256–264 (2011).

    Article  CAS  PubMed  Google Scholar 

  134. Rimoldi, M. et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nature Immunol. 6, 507–514 (2005).

    Article  CAS  Google Scholar 

  135. He, B. et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812–826 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Xu, W. et al. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nature Immunol. 8, 294–303 (2007).

    Article  CAS  Google Scholar 

  137. Iliev, I. D. et al. Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells. Gut 58, 1481–1489 (2009).

    Article  CAS  PubMed  Google Scholar 

  138. Ramakrishnan, L. Revisiting the role of the granuloma in tuberculosis. Nature Rev. Immunol. 12, 352–366 (2012).

    Article  CAS  Google Scholar 

  139. Mustafa, T., Mogga, S. J., Mfinanga, S. G., Morkve, O. & Sviland, L. Immunohistochemical analysis of cytokines and apoptosis in tuberculous lymphadenitis. Immunology 117, 454–462 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Popov, A. et al. Indoleamine 2,3-dioxygenase-expressing dendritic cells form suppurative granulomas following Listeria monocytogenes infection. J. Clin. Invest. 116, 3160–3170 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Shields, J. D., Kourtis, I. C., Tomei, A. A., Roberts, J. M. & Swartz, M. A. Induction of lymphoid-like stroma and immune escape by tumors that express the chemokine CCL21. Science 328, 749–752 (2010).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank S. Schwarzbaum for editing the manuscript. M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. This study was funded by the European Research Council Advanced grant and the FP7-HEALTH-2011 two-stage grant given to M.S.

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Author notes

  1. Ravid Shechter and Anat London: R.S. and A.L. contributed equally to this work.

Authors and Affiliations

  1. Anat London and Michal Schwartz are at the Department of Neurobiology, Ravid Shechter, Weizmann Institute of Science, Rehovot, Israel.,

    Ravid Shechter, Anat London & Michal Schwartz

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  1. Ravid Shechter
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Correspondence to Michal Schwartz.

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Glossary

Alternatively activated macrophages

(M2 macrophages). Macrophages that are stimulated by interleukin-4 (IL-4) or IL-13 and that express arginase 1, mannose receptor CD206 and IL-4 receptor. Other factors may also drive the alternative activation of macrophages. M2 macrophages have an anti-inflammatory function and mediate wound healing.

Amniotic sac

The sac in which the fetus develops. The sac is composed of a pair of tough but thin membranes: the inner membrane (the amnion) contains the amniotic fluid and the fetus, whereas the outer layer (the chorion) is part of the placenta.

Aqueous humour

Transparent gelatinous fluid that is similar to plasma and is secreted from the non-pigmented ciliary epithelium of the eye. It circulates from behind the iris (posterior chamber), where it is formed, to the front of the iris (anterior chamber), where it drains through the trabecular meshwork into Schlemm's canal, which is a venous sinus.

Central canal

A cerebrospinal fluid-filled tube that runs along the spinal cord and is continuous with the brain ventricular system.

Choroid plexus

A microvilli-enriched epithelioid structure within the roof of each one of the brain ventricles that creates a surface area comparable to that of the blood–brain barrier; its most well-characterized function is the production of cerebrospinal fluid, a 'clear' plasma fluid ultrafiltrate.

Ciliary body

A villous structure that is located behind the iris in the eye and produces the aqueous humour. Its stroma is coated by a double layer of ciliary epithelium; the inner layer is transparent, whereas the outer one is pigmented and forms a continuous layer with the retinal pigmented epithelium.

Circumventricular organs

Structures in the brain (including the area postrema, the subfornical organ, the organum vasculosum of the lamina terminalis and the median eminence) that, owing to their neuroendocrine functions, are considered as 'windows to the brain'. They contain fenestrated endothelium, are located at strategic positions in the ventricular system and are separated from the cerebrospinal fluid by a specialized blood–cerebrospinal fluid barrier.

Decidua

The specialized endometrial stromal tissue that encases the implanted conceptus. The decidua is predominantly comprised of decidual stromal cells, which differentiate from endometrial stromal cells following embryo implantation in the mouse. The decidua also contains various types of maternal leukocytes and makes direct contact with the trophoblasts on the outer surface of the conceptus to form the maternal–fetal interface.

Ependymal cells

The ependyma is a thin epithelial layer that lines the ventricular system of the brain and the central canal of the spinal cord. Ependymal cells are specialized cuboidal epithelial cells that contain cilia on their apical surfaces, which circulate the cerebrospinal fluid.

Glia limitans

An astrocyte structure that marks the border of the central nervous system parenchyma. It is composed of the parenchymal basement membrane and astrocyte endfeet, and covers the entire surface of the brain and spinal cord on external surfaces towards the leptomeningeal space (glia limitans superficialis) and internally towards the perivascular spaces (glia limitans perivascularis).

Microchimerism

The presence within one individual of a small population of cells from another genetically distinct individual.

Meninges

Vascularized tissue membranes that envelop superficial central nervous system areas and enclose the parenchyma. The meninges are composed of three layers: the outermost dura mater (beneath the skull), the arachnoid mater and the pia mater (the innermost layer, which is proximal to the parenchyma).

Rete testis

Tubules located in the mediastinum testis that carry sperm from the seminiferous tubules to the efferent ducts, which are the initial section of the epididymis. This is the site at which sperm is concentrated and fluids are absorbed.

Seminiferous tubule

A testicular structure in which meiosis and the subsequent creation of gametes (namely spermatozoa) takes place. There are two types of tubules: convoluted tubules are located towards the lateral end, whereas straight tubules are located towards the end that will exit the testis.

Sertoli cells

Tall (columnar type) epithelial niche-forming cells, the main function of which is to nourish the developing sperm through the stages of spermatogenesis (the process of differentiation of stem cells into mature germ cells). They also consume the residual cytoplasm and engulf excess spermatozoa. The tight junctions of Sertoli cells form the blood–testis barrier, which separates the abluminal compartment of the seminiferous tubule from the blood.

Subarachnoid space

The gap between the meningeal arachnoid membrane and the innermost pia mater. This cerebrospinal fluid-filled space is traversed by blood vessels.

Tight junctions

A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight-junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonulaoccludin proteins.

Tolerance

A term that denotes lymphocyte non-responsiveness to antigen but implies an active process rather than passive indifference.

Trophoblasts

Specialized cells forming the outer layer of blastocytes; these cells develop to form most of the placenta, where they function in embryo implantation and the interaction with the decidualized maternal uterus.

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Shechter, R., London, A. & Schwartz, M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol 13, 206–218 (2013). https://doi.org/10.1038/nri3391

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