It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity1,2,3,4 and immunoregulation5,6. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells7,8, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (TEM) found only in the lungs and small intestine. Additionally, regulatory T (Treg) cells comprise a high proportion (30–40%) of CD4+ T cells in pediatric tissues but are present at much lower frequencies (1–10%) in adult tissues. Pediatric tissue Treg cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest Treg:TEM cell ratios, which suggests control in situ of immune responses in early life.
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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).
Schenkel, J.M. et al. T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).
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).
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).
Burzyn, D., Benoist, C. & Mathis, D. Regulatory T cells in nonlymphoid tissues. Nat. Immunol. 14, 1007–1013 (2013).
Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013).
Sathaliyawala, T. et al. Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets. Immunity 38, 187–197 (2013).
Thome, J.J.C. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).
Gibbons, D. et al. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat. Med. 20, 1206–1210 (2014).
Chalmers, I.M., Janossy, G., Contreras, M. & Navarrete, C. Intracellular cytokine profile of cord and adult blood lymphocytes. Blood 92, 11–18 (1998).
Peoples, J.D. et al. Neonatal cord blood subsets and cytokine response to bacterial antigens. Am. J. Perinatol. 26, 647–657 (2009).
Mold, J.E. et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322, 1562–1565 (2008).
Zhang, X. et al. CD4 T cells with effector memory phenotype and function develop in the sterile environment of the fetus. Sci. Transl. Med. 6, 238ra72 (2014).
Farber, D.L., Yudanin, N.A. & Restifo, N.P. Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24–35 (2014).
Thome, J.J. & Farber, D.L. Emerging concepts in tissue-resident T cells: lessons from humans. Trends Immunol. 36, 428–435 (2015).
Kimmig, S. et al. Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J. Exp. Med. 195, 789–794 (2002).
Shiow, L.R. et al. CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440, 540–544 (2006).
Laidlaw, B.J. et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633–645 (2014).
Ohkura, N., Kitagawa, Y. & Sakaguchi, S. Development and maintenance of regulatory T cells. Immunity 38, 414–423 (2013).
Chaudhry, A. & Rudensky, A.Y. Control of inflammation by integration of environmental cues by regulatory T cells. J. Clin. Invest. 123, 939–944 (2013).
Verbsky, J.W. & Chatila, T.A. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr. Opin. Pediatr. 25, 708–714 (2013).
Pesenacker, A.M., Broady, R. & Levings, M.K. Control of tissue-localized immune responses by human regulatory T cells. Eur. J. Immunol. 45, 333–343 (2015).
Ferraro, A. et al. Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes 60, 2903–2913 (2011).
Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).
Seddiki, N. et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J. Exp. Med. 203, 1693–1700 (2006).
Seddiki, N. et al. Persistence of naive CD45RA+ regulatory T cells in adult life. Blood 107, 2830–2838 (2006).
Valmori, D., Merlo, A., Souleimanian, N.E., Hesdorffer, C.S. & Ayyoub, M. A peripheral circulating compartment of natural naive CD4+ Tregs . J. Clin. Invest. 115, 1953–1962 (2005).
Booth, N.J. et al. Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J. Immunol. 184, 4317–4326 (2010).
Allan, S.E., Song-Zhao, G.X., Abraham, T., McMurchy, A.N. & Levings, M.K. Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3. Eur. J. Immunol. 38, 3282–3289 (2008).
Yang, S., Fujikado, N., Kolodin, D., Benoist, C. & Mathis, D. Immune tolerance. Regulatory T cells generated early in life play a distinct role in maintaining self-tolerance. Science 348, 589–594 (2015).
This work was supported by the US National Institutes of Health (NIH) (grant no. AI100119; D.L.F., AI106697: D.L.F., F31AG047003; J.J.C.T., AI083022; K.L.B.) and a BD Bioscience Research Grant (J.J.C.T.). These studies were performed in the Columbia Center for Translational Immunology (CCTI) Flow Cytometry Core, funded in part through an S10 Shared Instrumentation Grant from the NIH (grant no. S10RR027050), with the excellent technical assistance of S.-H. Ho. We gratefully acknowledge the generosity of the organ donor families and the efforts of the LiveOnNY transplant coordinators and staff for making this study possible. We also wish to thank S. Mickel and B. Kumar for their assistance with tissue processing, B. Levin and N. Yudanin for their assistance with statistical analyses and K. Zens, N. Yudanin and E. Lamouse-Smith for critical reading of this manuscript.
The authors declare no competing financial interests.
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Thome, J., Bickham, K., Ohmura, Y. et al. Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat Med 22, 72–77 (2016). https://doi.org/10.1038/nm.4008
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