Abstract

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , & Natural autoantibodies to apoptotic cell membranes regulate fundamental innate immune functions and suppress inflammation. Discov. Med. 8, 151–156 (2009).

  2. 2.

    et al. B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity 21, 379–390 (2004).

  3. 3.

    et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science 286, 2156–2159 (1999).

  4. 4.

    et al. B-1 and B-2 cell-derived immunoglobulin M antibodies are nonredundant components of the protective response to influenza virus infection. J. Exp. Med. 192, 271–280 (2000).

  5. 5.

    , , & B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity 23, 7–18 (2005).

  6. 6.

    , , , & A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection. J. Exp. Med. 188, 2381–2386 (1998).

  7. 7.

    , & Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14, 617–629 (2001).

  8. 8.

    , , & The omentum. World J. Gastroenterol. 6, 169–176 (2000).

  9. 9.

    , & CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity 16, 67–76 (2002).

  10. 10.

    , & Lymphocytes in the peritoneum home to the omentum and are activated by resident dendritic cells. J. Immunol. 183, 1155–1165 (2009).

  11. 11.

    et al. Regulation of B1 cell migration by signals through Toll-like receptors. J. Exp. Med. 203, 2541–2550 (2006).

  12. 12.

    et al. Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30, 731–743 (2009).

  13. 13.

    , , , & Characterization of mouse mediastinal fat-associated lymphoid clusters. Cell Tissue Res. 357, 731–741 (2014).

  14. 14.

    et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).

  15. 15.

    et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl. Acad. Sci. USA 107, 11489–11494 (2010).

  16. 16.

    et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).

  17. 17.

    et al. Innate lymphoid cells–a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).

  18. 18.

    , & Development of secondary lymphoid organs. Annu. Rev. Immunol. 26, 627–650 (2008).

  19. 19.

    & Stromal cell-immune cell interactions. Annu. Rev. Immunol. 29, 23–43 (2011).

  20. 20.

    & Secondary lymphoid organs: responding to genetic and environmental cues in ontogeny and the immune response. J. Immunol. 183, 2205–2212 (2009).

  21. 21.

    et al. Lymphotoxin α/β and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. J. Exp. Med. 189, 403–412 (1999).

  22. 22.

    et al. Follicular dendritic cells emerge from ubiquitous perivascular precursors. Cell 150, 194–206 (2012).

  23. 23.

    et al. Distinct roles of lymphotoxin α and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from non-bone marrow-derived cells. J. Exp. Med. 186, 1997–2004 (1997).

  24. 24.

    et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000).

  25. 25.

    , , & B lymphocytes induce the formation of follicular dendritic cell clusters in a lymphotoxin α-dependent fashion. J. Exp. Med. 187, 1009–1018 (1998).

  26. 26.

    et al. Antigen-specific memory in B-1a and its relationship to natural immunity. Proc. Natl. Acad. Sci. USA 109, 5388–5393 (2012).

  27. 27.

    et al. Antigen-specific antibody responses in B-1a and their relationship to natural immunity. Proc. Natl. Acad. Sci. USA 109, 5382–5387 (2012).

  28. 28.

    , & Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat. Rev. Immunol. 13, 101–117 (2013).

  29. 29.

    et al. The capsular polysaccharide Vi from Salmonella typhi is a B1b antigen. J. Immunol. 189, 5527–5532 (2012).

  30. 30.

    et al. The porin OmpD from nontyphoidal Salmonella is a key target for a protective B1b cell antibody response. Proc. Natl. Acad. Sci. USA 106, 9803–9808 (2009).

  31. 31.

    & Generation of B cell memory to the bacterial polysaccharide α-1,3 dextran. J. Immunol. 183, 6359–6368 (2009).

  32. 32.

    , , , & A quasi-monoclonal mouse. Science 272, 1649–1652 (1996).

  33. 33.

    et al. Early B blasts acquire a capacity for Ig class switch recombination that is lost as they become plasmablasts. Eur. J. Immunol. 41, 3506–3512 (2011).

  34. 34.

    et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).

  35. 35.

    , , , & The lymphotoxin β receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9, 59–70 (1998).

  36. 36.

    et al. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).

  37. 37.

    & A role for tumor necrosis factor receptor type 1 in gut-associated lymphoid tissue development: genetic evidence of synergism with lymphotoxin β. J. Exp. Med. 187, 1977–1983 (1998).

  38. 38.

    et al. Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling. J. Immunol. 177, 6824–6832 (2006).

  39. 39.

    et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

  40. 40.

    et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168, 57–64 (2002).

  41. 41.

    , , & Role of the gut microbiota in immunity and inflammatory disease. Nat. Rev. Immunol. 13, 321–335 (2013).

  42. 42.

    et al. Short term high fat diet challenge promotes alternative macrophage polarization in adipose tissue via natural killer T cells and interleukin-4. J. Biol. Chem. 287, 24378–24386 (2012).

  43. 43.

    et al. Activation of natural killer T cells promotes M2 macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J. Biol. Chem. 287, 13561–13571 (2012).

  44. 44.

    et al. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37, 574–587 (2012).

  45. 45.

    et al. Natural killer T cells in adipose tissue prevent insulin resistance. J. Clin. Invest. 122, 3343–3354 (2012).

  46. 46.

    et al. Activation of invariant natural killer T cells by lipid excess promotes tissue inflammation, insulin resistance, and hepatic steatosis in obese mice. Proc. Natl. Acad. Sci. USA 109, E1143–E1152 (2012).

  47. 47.

    et al. Initiation of NALT organogenesis is independent of the IL-7R, LTβR, and NIK signaling pathways but requires the Id2 gene and CD3CD4+CD45+ cells. Immunity 17, 31–40 (2002).

  48. 48.

    et al. Lymphotoxin-β receptor signaling through NF-κB2-RelB pathway reprograms adipocyte precursors as lymph node stromal cells. Immunity 37, 721–734 (2012).

  49. 49.

    et al. Native adipose stromal cells egress from adipose tissue in vivo: evidence during lymph node activation. Stem Cells 31, 1309–1320 (2013).

  50. 50.

    , , , & Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387–398 (1999).

  51. 51.

    et al. Tracking germinal center B cells expressing germ-line immunoglobulin γ1 transcripts by conditional gene targeting. Proc. Natl. Acad. Sci. USA 103, 7396–7401 (2006).

  52. 52.

    , , , & A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007).

  53. 53.

    et al. Distinct and nonredundant in vivo functions of TNF produced by t cells and macrophages/neutrophils: protective and deleterious effects. Immunity 22, 93–104 (2005).

  54. 54.

    et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).

Download references

Acknowledgements

We thank the personnel of the Biomedical Services Unit of the University of Birmingham for animal colony care; E. Jenkinson for support; G. Anderson, P. Lane, and A. Rot for comments on the manuscript; C. Buckley for facilitating animal procedures; R. Bird for cell sorting; K. Pfeffer (Heinrich Heine University) for Ltbr−/− mice; G. Eberl (Institut Pasteur) for tissues from germ-free mice; D. Finke (University of Basel) for tissues from Cxcr5−/− mice; A. Diefenback (University of Mainz) for tissues from Id2CreErt2/+Gt(ROSA)26SorYFP/+Gata3f/f mice; and the US National Institutes of Health Tetramer Facility for CD1d-PBS-57 loaded tetramers. Supported by the European Union Framework Programme 7 integrated project INFLACARE (J.H.C.); the Biotechnology and Biological Sciences Research Council (BB/K004900/1 to J.H.C.) and the College of Medical and Dental Sciences of the University of Birmingham (J.H.C.); the American Asthma Foundation, the UK Medical Research Council and the Wellcome Trust (100963/Z/13/Z) for work in the A. McKenzie laboratory; the Biotechnology and Biological Sciences Research Council institute synergy programme, the European Research Council (280307) and the Agency for Science, Technology and Research (to Y.L.) for work in the M. Veldhoen laboratory; Deutsche Forschungsgemeinschaf (NE1466/2-1), the Russian Science Foundation (14-50-00060) and the Russian Foundation for Basic Research (13-04-40268 to A.A.K.) for work in the S. Nedospasov laboratory; the European Research Council (340217-MCs_inTEST) for work in the G. Kollias laboratory; the Medical Research Council (S.N.); the UK Medical Research Council (MRC/K01207X/1 to L.H.J.); and the Lifelong Health and Wellbeing cross council initiative (Topjabs G1001390 for K.M.T., Y.Z. and J.M.).

Author information

Author notes

    • Cécile Bénézech
    •  & Lucy H Jones

    Present address: BHF/UoE Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK.

    • Nguyet-Thin Luu
    •  & Jennifer A Walker

    These authors contributed equally to this work.

Affiliations

  1. School of Immunity and Infection, IBR-MRC Centre for Immune Regulation, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.

    • Cécile Bénézech
    • , Nguyet-Thin Luu
    • , Kyoko Nakamura
    • , Yang Zhang
    • , Saba Nayar
    • , Adriana Flores-Langarica
    • , Alistair McIntosh
    • , Jennifer Marshall
    • , Francesca Barone
    • , Adam F Cunningham
    • , David R Withers
    • , Kai Michael Toellner
    • , Nick D Jones
    •  & Jorge H Caamaño
  2. MRC Laboratory of Molecular Biology, Cambridge, UK.

    • Jennifer A Walker
    •  & Andrew N J McKenzie
  3. Inflammation Biology, German Rheumatism Research Center, Leibniz Institute, Berlin, Germany.

    • Andrei A Kruglov
    •  & Sergei A Nedospasov
  4. Engelhardt Institute of Molecular Biology, Moscow, Russia.

    • Andrei A Kruglov
    •  & Sergei A Nedospasov
  5. Lomonosov Moscow State University, Moscow, Russia.

    • Andrei A Kruglov
    •  & Sergei A Nedospasov
  6. Lymphocyte Signalling and Development Programme, The Babraham Institute, Cambridge, UK.

    • Yunhua Loo
    •  & Marc Veldhoen
  7. Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK.

    • Lucy H Jones
    •  & Judith E Allen
  8. College of Life and Environmental Sciences, University of Birmingham, Birmingham, UK.

    • Gurdyal Besra
  9. Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.

    • Katherine Miles
    •  & Mohini Gray
  10. Division of Immunology, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece.

    • George Kollias
  11. Departament of Experimental Physiology, National and Kapodistrian University of Athens, Athens, Greece.

    • George Kollias

Authors

  1. Search for Cécile Bénézech in:

  2. Search for Nguyet-Thin Luu in:

  3. Search for Jennifer A Walker in:

  4. Search for Andrei A Kruglov in:

  5. Search for Yunhua Loo in:

  6. Search for Kyoko Nakamura in:

  7. Search for Yang Zhang in:

  8. Search for Saba Nayar in:

  9. Search for Lucy H Jones in:

  10. Search for Adriana Flores-Langarica in:

  11. Search for Alistair McIntosh in:

  12. Search for Jennifer Marshall in:

  13. Search for Francesca Barone in:

  14. Search for Gurdyal Besra in:

  15. Search for Katherine Miles in:

  16. Search for Judith E Allen in:

  17. Search for Mohini Gray in:

  18. Search for George Kollias in:

  19. Search for Adam F Cunningham in:

  20. Search for David R Withers in:

  21. Search for Kai Michael Toellner in:

  22. Search for Nick D Jones in:

  23. Search for Marc Veldhoen in:

  24. Search for Sergei A Nedospasov in:

  25. Search for Andrew N J McKenzie in:

  26. Search for Jorge H Caamaño in:

Contributions

C.B., N.-T.L., J.A.W., A.A.K., Y.L., K.N., Y.Z., S.N., L.H.J. and J.H.C. designed and performed the research and collected and analyzed the data; A.F.-L., A.M., J.M., F.B., G.B., K.M., J.E.A., M.G., G.K., A.F.C., D.R.W., K.M.T., N.D.J., M.V., S.A.N. and A.N.J.M. facilitated the research; and C.B. and J.H.C. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Cécile Bénézech or Jorge H Caamaño.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–6 and Supplementary Table 1

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ni.3215

Further reading

Newsletter Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing