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

Nature Immunology volume 21, pages 412–421 (2020)Cite this article

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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.

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Data availability

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

References

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

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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).

Author information

Author notes

  1. Raissa Fonseca

    Present address: Department of Microbiology and Immunology, University of Melbourne and the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

  2. Lalit K. Beura

    Present address: Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA

  3. Hazem E. Ghoneim

    Present address: Department of Microbial Infection and Immunity, College of Medicine, Ohio State University, Columbus, OH, USA

  4. These authors contributed equally: Raissa Fonseca, Lalit K. Beura, Clare F. Quarnstrom.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA

    Raissa Fonseca, Lalit K. Beura, Clare F. Quarnstrom, Milcah C. Scott, Nancy J. Fares-Frederickson, Sathi Wijeyesinghe, Emily A. Thompson, Vaiva Vezys & David Masopust

  2. Department of Immunology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Hazem E. Ghoneim, Caitlin C. Zebley & Benjamin Youngblood

  3. Department of Computational Biology, St Jude Children’s Research Hospital, Memphis, TN, USA

    Yiping Fan

  4. Department of Laboratory Medicine and Pathology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA

    Henrique Borges da Silva

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Contributions

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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