Developmental plasticity allows outside-in immune responses by resident memory T cells

Abstract

Central memory T (TCM) cells patrol lymph nodes and perform conventional memory responses on restimulation: proliferation, migration and differentiation into diverse T cell subsets while also self-renewing. Resident memory T (TRM) cells are parked within single organs, share properties with terminal effectors and contribute to rapid host protection. We observed that reactivated TRM cells rejoined the circulating pool. Epigenetic analyses revealed that TRM cells align closely with conventional memory T cell populations, bearing little resemblance to recently activated effectors. Fully differentiated TRM cells isolated from small intestine epithelium exhibited the potential to differentiate into TCM cells, effector memory T cells and TRM cells on recall. Ex-TRM cells, former intestinal TRM cells that rejoined the circulating pool, heritably maintained a predilection for homing back to their tissue of origin on subsequent reactivation and a heightened capacity to redifferentiate into TRM cells. Thus, TRM cells can rejoin the circulation but are advantaged to re-form local TRM when called on.

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Fig. 1: Local reactivation of TRM cells precipitates egress to circulation.
Fig. 2: Epigenetic profiling of TRM cells reveals memory state with potential developmental plasticity.
Fig. 3: Transdifferentiation of TRM cells into circulating memory T cell subsets.
Fig. 4: Developmental plasticity and tissue redistribution of TCM and TRM cells.
Fig. 5: Ex-TRM cells remain epigenetically poised for migration and TRM cell redifferentiation.
Fig. 6: Ex-TRM cells are poised to reacquire TRM cell characteristics in response to cytokines.

Data availability

All original data are available from the corresponding author upon request.

References

  1. 1.

    Obar, J. J., Khanna, K. M. & Lefrançois, L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859–869 (2008).

  2. 2.

    Picker, L. J. & Butcher, E. C. Physiological and molecular mechanisms of lymphocyte homing. Annu. Rev. Immunol. 10, 561–591 (1992).

  3. 3.

    von Andrian, U. H. & Mackay, C. R. T-cell function and migration—two sides of the same coin. N. Engl. J. Med. 343, 1020–1034 (2000).

  4. 4.

    Masopust, D. & Soerens, A. G. Tissue-resident T cells and other resident leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).

  5. 5.

    Park, C. O. & Kupper, T. S. The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat. Med. 21, 688–697 (2015).

  6. 6.

    Reinhardt, R. L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M. K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).

  7. 7.

    Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009).

  8. 8.

    Masopust, D., Vezys, V., Marzo, A. L. & Lefrançois, L. Preferential localization of effector memory cells in nonlymphoid tissue. Science 291, 2413–2417 (2001).

  9. 9.

    Champagne, P. et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410, 106–111 (2001).

  10. 10.

    Stemberger, C. et al. Stem cell-like plasticity of naïve and distinct memory CD8+ T cell subsets. Semin. Immunol. 21, 62–68 (2009).

  11. 11.

    Farber, D. L., Yudanin, N. A. & Restifo, N. P. Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24–35 (2014).

  12. 12.

    Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).

  13. 13.

    Youngblood, B. et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552, 404–409 (2017).

  14. 14.

    Mueller, S. N., Gebhardt, T., Carbone, F. R. & Heath, W. R. Memory T cell subsets, migration patterns, and tissue residence. Annu. Rev. Immunol. 31, 137–161 (2013).

  15. 15.

    Gerlach, C. et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284 (2016).

  16. 16.

    Vezys, V. et al. Memory CD8 T-cell compartment grows in size with immunological experience. Nature 457, 196–199 (2009).

  17. 17.

    Shin, H. & Iwasaki, A. Tissue-resident memory T cells. Immunol. Rev. 255, 165–181 (2013).

  18. 18.

    Nguyen, Q. P., Deng, T. Z., Witherden, D. A. & Goldrath, A. W. Origins of CD4+ circulating and tissue-resident memory T-cells. Immunology 157, 3–12 (2019).

  19. 19.

    Szabo, P. A., Miron, M. & Farber, D. L. Location, location, location: tissue resident memory T cells in mice and humans. Sci. Immunol. 4, eaas9673 (2019).

  20. 20.

    Glennie, N. D. et al. Skin-resident memory CD4+ T cells enhance protection against Leishmania major infection. J. Exp. Med. 212, 1405–1414 (2015).

  21. 21.

    Kadoki, M. et al. Organism-level analysis of vaccination reveals networks of protection across tissues. Cell 171, 398–413.e21 (2017).

  22. 22.

    Casey, K. A. et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 188, 4866–4875 (2012).

  23. 23.

    Cheroutre, H. IELs: enforcing law and order in the court of the intestinal epithelium. Immunol. Rev. 206, 114–131 (2005).

  24. 24.

    Wakim, L. M., Waithman, J., van Rooijen, N., Heath, W. R. & Carbone, F. R. Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science 319, 198–202 (2008).

  25. 25.

    Park, S. L. et al. Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Nat. Immunol. 19, 183–191 (2018).

  26. 26.

    Beura, L. K. et al. Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat. Immunol. 19, 173–182 (2018).

  27. 27.

    Schenkel, J. M., Fraser, K. A., Vezys, V. & Masopust, D. Sensing and alarm function of resident memory CD8+ T cells. Nat. Immunol. 14, 509–513 (2013).

  28. 28.

    Beura, L. K. et al. Cells in nonlymphoid tissues give rise to lymph-node-resident memory T cells. Immunity 48, 327–338.e5 (2018).

  29. 29.

    Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).

  30. 30.

    Brinkmann, V., Cyster, J. G. & Hla, T. FTY720: sphingosine 1-phosphate receptor-1 in the control of lymphocyte egress and endothelial barrier function. Am. J. Transplant. 4, 1019–1025 (2004).

  31. 31.

    Schenkel, J. M. et al. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).

  32. 32.

    Masopust, D., Vezys, V., Wherry, E. J., Barber, D. L. & Ahmed, R. Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J. Immunol. 176, 2079–2083 (2006).

  33. 33.

    Watanabe, R. et al. Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci. Transl. Med. 7, 279ra39 (2015).

  34. 34.

    Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van der Most, R. & Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911–4927 (2003).

  35. 35.

    Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).

  36. 36.

    Kersh, E. N. et al. Rapid demethylation of the IFN-γ gene occurs in memory but not naive CD8 T cells. J. Immunol. 176, 4083–4093 (2006).

  37. 37.

    Malta, T. M. et al. Machine learning identifies stemness features associated with oncogenic dedifferentiation. Cell 173, 338–354.e15 (2018).

  38. 38.

    Mackay, L. K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).

  39. 39.

    Sheridan, B. S. et al. Oral infection drives a distinct population of intestinal resident memory CD8+ T cells with enhanced protective function. Immunity 40, 747–757 (2014).

  40. 40.

    Herndler-Brandstetter, D. et al. KLRG1+ effector CD8+ T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity 48, 716–729.e8 (2018).

  41. 41.

    Hofmann, M. & Pircher, H. E-cadherin promotes accumulation of a unique memory CD8 T-cell population in murine salivary glands. Proc. Natl Acad. Sci. USA 108, 16741–16746 (2011).

  42. 42.

    Teijaro, J. R. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510–5514 (2011).

  43. 43.

    Skon, C. N. et al. Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 14, 1285–1293 (2013).

  44. 44.

    Cahill, R. N. P., Poskitt, D. C., Frost, H. & Trnka, Z. Two distinct pools of recirculating T lymphocytes: migratory characteristics of nodal and intestinal T lymphocytes. J. Exp. Med. 145, 420–428 (1977).

  45. 45.

    Mackay, C. R., Marston, W. L. & Dudler, L. Naive and memory T cells show distinct pathways of lymphocyte recirculation. J. Exp. Med. 171, 801–817 (1990).

  46. 46.

    Collins, N. et al. Skin CD4+ memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation. Nat. Commun. 7, 11514 (2016).

  47. 47.

    Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).

  48. 48.

    Klicznik, M. M. et al. Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy individuals. Sci. Immunol. 4, eaav8995 (2019).

  49. 49.

    Diani, M. et al. Increased frequency of activated CD8+ T cell effectors in patients with psoriatic arthritis. Sci. Rep. 9, 10870 (2019).

  50. 50.

    Han, A. et al. Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease. Proc. Natl Acad. Sci. USA 110, 13073–13078 (2013).

  51. 51.

    Anderson, K. G. et al. Intravascular staining for discrimination of vascular and tissue leukocytes. Nat. Protoc. 9, 209–222 (2014).

  52. 52.

    Thompson, E. A., Beura, L. K., Nelson, C. E., Anderson, K. G. & Vezys, V. Shortened intervals during heterologous boosting preserve memory CD8 T cell function but compromise longevity. J. Immunol. 196, 3054–3063 (2016).

  53. 53.

    Silva, K. A. & Sundberg, J. P. Surgical methods for full-thickness skin grafts to induce alopecia areata in C3H/HeJ mice. Comp. Med. 63, 392–397 (2013).

  54. 54.

    Trinh, B. N., Long, T. I. & Laird, P. W. DNA methylation analysis by MethyLight technology. Methods 25, 456–462 (2001).

  55. 55.

    Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157.e19 (2017).

  56. 56.

    Sokolov, A., Carlin, D. E., Paull, E. O., Baertsch, R. & Stuart, J. M. Pathway-based genomics prediction using generalized elastic net. PLoS Comput. Biol. 12, e1004790 (2016).

  57. 57.

    Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold changes and dispersion for RNA-seq data with Deseq2. Genome Biol. 15, 550 (2014).

  58. 58.

    Pallett, L. J. et al. IL-2high tissue-resident T cells in the human liver: sentinels for hepatotropic infection. J. Exp. Med. 214, 1567–1580 (2017).

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Acknowledgements

We thank the members of the Masopust laboratory and the University of Minnesota Center for Immunology for helpful discussions. We were funded by a National Institutes of Health grant (no. R01AI084913), the Howard Hughes Medical Institute Scholars program (to D.M.) and an FAPESP-BEPE (2015/00680-7) fellowship (to R.F).

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R.F., L.K.B., C.F.Q., N.J.F.-F., S.W., E.A.T. and H.B.S. performed and analyzed the experiments. H.E.G. and Y.F. performed and analyzed the WGBS. C.C.Z. and M.C.S. conducted the bioinformatics analysis. R.F., L.K.B., C.F.Q., N.J.F.-F., V.V., B.Y. and D.M. designed the experiments and prepared the manuscript. D.M. was responsible for research supervision, coordination and strategy.

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Correspondence to David Masopust.

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Fonseca, R., Beura, L.K., Quarnstrom, C.F. et al. Developmental plasticity allows outside-in immune responses by resident memory T cells. Nat Immunol 21, 412–421 (2020). https://doi.org/10.1038/s41590-020-0607-7

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