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Some naïve T cell fates are sealed

Tissue-resident memory T (TRM) cells constitute a subpopulation of memory cells that reside in tissues instead of recirculating. CD8+ epithelial TRM (eTRM) cells, which occupy the epithelium of sites like the skin, require transforming growth factor–β (TGF-β) for their development. Mani et al. found that αV integrin–expressing dendritic cells, which activate and present TGF-β, are key (see the Perspective by Farber). Surprisingly, this interplay did not occur in the skin or draining lymph nodes during T cell priming. Rather, resting naïve CD8+ T cells interacted with αV integrin–expressing migratory dendritic cells during immune homeostasis, reversibly preconditioning them to become eTRM cells upon activation. A potent cytokine is thus controlled in a context-dependent manner and preimmune T cell repertoires may be less uniform than previously presumed.
Science, this issue p. eaav5728; see also p. 188

Structured Abstract

INTRODUCTION

Successful immune responses to infections generate memory T cells that provide enhanced protection from reinfection by the same pathogen. Some memory cells continually recirculate through tissues via the blood and lymph, whereas others establish local residence. This second population includes CD8+ tissue-resident memory T cells that seed the epithelial layers of barrier tissues (eTRM cells), such as the skin. These cells constitute a highly sensitive sentinel system, which responds to reencounters with cognate pathogen-derived antigens by triggering a local inflammatory response to rapidly contain the infection. The formation of eTRM cells requires transforming growth factor β (TGF-β), a broadly expressed cytokine with a wide range of functions in the immune system. Secreted TGF-β is abundant in tissues, but its biological activity is tightly regulated by release of the active cytokine from the latent pro-complex. Binding to αV-integrins facilitates TGF-β release for activity in the immune system. However, the cellular mechanisms of its release, as well as the sites of CD8+ T cell exposure driving the formation of eTRM cells, are unknown.

RATIONALE

Enhancing eTRM cell formation is desirable in the context of vaccines designed to protect against pathogens that infect by way of barrier tissues. Conversely, attenuating eTRM cell formation may be therapeutic for diseases, such as psoriasis, in which eTRM cells play pathogenic roles. Understanding how TGF-β is activated and where it acts on T cells to enable eTRM differentiation may inform new approaches to selectively amplify or disrupt this process without the predicted systemic effects of globally perturbing TGF-β activity. We hypothesized that αV-integrin–expressing dendritic cells (DCs) activate and present TGF-β to CD8+ T cells to enable eTRM cell formation.

RESULTS

Upon deleting αV integrins from CD11c+ DCs in mice, we observed a pronounced reduction in the number of CD8+ T cells in the epidermis, whereas the numbers of dermal CD8+ T cells and other skin immune cells were unchanged. The same selective defect was apparent after different forms of skin immune challenge, including DNA vaccination, indicating that the de novo formation of eTRM cells was disrupted. Unexpectedly, neither expression of αV integrins on DCs in skin-draining lymph nodes during priming of T cell responses, nor on DCs in the skin, was required for generation of eTRM cells. Instead, the exposure of resting naïve CD8+ T cells to αV-expressing DCs during immune homeostasis preconditioned them for effective formation of eTRM cells upon activation. An examination of the genomic accessibility of naïve cells suggested that TGF-β signals enabled by αV-expressing DCs prime genes involved in eTRM cell formation for their more rapid induction. This reversible preconditioning effect was mediated by migratory DCs and occurred in lymph nodes, but not in spleen, as both exposure of naïve T cells to TGF-β and the formation of eTRM cells in the skin were strongly impaired in the absence of lymph nodes or of CCR7-dependent DC migration from skin to lymph nodes. eTRM formation was also reduced when expression of major histocompatibility complex class I (MHC I) molecules and αV integrins was segregated on individual DCs, indicating that exposure of naïve CD8+ T cells to TGF-β occurs in the context of noncognate, yet MHC I–dependent, physical interactions with migratory DCs.

CONCLUSION

Naïve CD8+ T cells are preconditioned for the formation of skin eTRM cells by DCs that migrate from nonlymphoid tissues to lymph nodes at steady state. These DCs both activate and present TGF-β to naïve T cells, exemplifying how this cytokine’s potent biological activities can be limited to specific contexts through its requirement for extracellular processing. In this way, individual T cells appear to be actively preconditioned for a specific differentiation path already at the naïve cell stage. This is in contrast to the general expectation that the preimmune T cell repertoire is uniform in its potential to differentiate into various effector and memory cell subsets upon activation.
Migratory DCs activate TGF-β in lymph nodes to precondition naïve CD8+ T cells for eTRM cell formation.
During homeostasis, migratory DCs that express αV integrins, including αVβ8, but not resident DCs, activate TGF-β and present it to naïve CD8+ T cells (TN) during noncognate interactions. Preconditioned naïve T cells then effectively become epithelial resident memory T (eTRM) cells upon immune challenge.

Abstract

Epithelial resident memory T (eTRM) cells serve as sentinels in barrier tissues to guard against previously encountered pathogens. How eTRM cells are generated has important implications for efforts to elicit their formation through vaccination or prevent it in autoimmune disease. Here, we show that during immune homeostasis, the cytokine transforming growth factor β (TGF-β) epigenetically conditions resting naïve CD8+ T cells and prepares them for the formation of eTRM cells in a mouse model of skin vaccination. Naïve T cell conditioning occurs in lymph nodes (LNs), but not in the spleen, through major histocompatibility complex class I–dependent interactions with peripheral tissue–derived migratory dendritic cells (DCs) and depends on DC expression of TGF-β–activating αV integrins. Thus, the preimmune T cell repertoire is actively conditioned for a specialized memory differentiation fate through signals restricted to LNs.

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Supplementary Material

Summary

Figs. S1 to S6
Tables S1 and S2

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References and Notes

1
D. Masopust, A. G. Soerens, Tissue-Resident T Cells and Other Resident Leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).
2
S. N. Mueller, L. K. Mackay, Tissue-resident memory T cells: Local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).
3
T. Gebhardt, U. Palendira, D. C. Tscharke, S. Bedoui, Tissue-resident memory T cells in tissue homeostasis, persistent infection, and cancer surveillance. Immunol. Rev. 283, 54–76 (2018).
4
T. Gebhardt, L. M. Wakim, L. Eidsmo, P. C. Reading, W. R. Heath, F. R. Carbone, Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009).
5
S. Ariotti, M. A. Hogenbirk, F. E. Dijkgraaf, L. L. Visser, M. E. Hoekstra, J.-Y. Song, H. Jacobs, J. B. Haanen, T. N. Schumacher, T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101–105 (2014).
6
J. M. Schenkel, K. A. Fraser, L. K. Beura, K. E. Pauken, V. Vezys, D. Masopust, Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).
7
L. K. Mackay, A. Rahimpour, J. Z. Ma, N. Collins, A. T. Stock, M.-L. Hafon, J. Vega-Ramos, P. Lauzurica, S. N. Mueller, T. Stefanovic, D. C. Tscharke, W. R. Heath, M. Inouye, F. R. Carbone, T. Gebhardt, The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).
8
D. Masopust, D. Choo, V. Vezys, E. J. Wherry, J. Duraiswamy, R. Akondy, J. Wang, K. A. Casey, D. L. Barber, K. S. Kawamura, K. A. Fraser, R. J. Webby, V. Brinkmann, E. C. Butcher, K. A. Newell, R. Ahmed, Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).
9
B. J. Laidlaw, N. Zhang, H. D. Marshall, M. M. Staron, T. Guan, Y. Hu, L. S. Cauley, J. Craft, S. M. Kaech, CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633–645 (2014).
10
L. K. Mackay, E. Wynne-Jones, D. Freestone, D. G. Pellicci, L. A. Mielke, D. M. Newman, A. Braun, F. Masson, A. Kallies, G. T. Belz, F. R. Carbone, T-box Transcription Factors Combine with the Cytokines TGF-β and IL-15 to Control Tissue-Resident Memory T Cell Fate. Immunity 43, 1101–1111 (2015).
11
J. J. Milner, C. Toma, B. Yu, K. Zhang, K. Omilusik, A. T. Phan, D. Wang, A. J. Getzler, T. Nguyen, S. Crotty, W. Wang, M. E. Pipkin, A. W. Goldrath, Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. Nature 552, 253–257 (2017).
12
I. B. Robertson, D. B. Rifkin, Regulation of the Bioavailability of TGF-β and TGF-β-Related Proteins. Cold Spring Harb. Perspect. Biol. 8, a021907 (2016).
13
M. A. Travis, D. Sheppard, TGF-β activation and function in immunity. Annu. Rev. Immunol. 32, 51–82 (2014).
14
J. Mohammed, L. K. Beura, A. Bobr, B. Astry, B. Chicoine, S. W. Kashem, N. E. Welty, B. Z. Igyártó, S. Wijeyesinghe, E. A. Thompson, C. Matte, L. Bartholin, A. Kaplan, D. Sheppard, A. G. Bridges, W. D. Shlomchik, D. Masopust, D. H. Kaplan, Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β. Nat. Immunol. 17, 414–421 (2016).
15
A. Lacy-Hulbert, A. M. Smith, H. Tissire, M. Barry, D. Crowley, R. T. Bronson, J. T. Roes, J. S. Savill, R. O. Hynes, Ulcerative colitis and autoimmunity induced by loss of myeloid αv integrins. Proc. Natl. Acad. Sci. U.S.A. 104, 15823–15828 (2007).
16
M. L. Caton, M. R. Smith-Raska, B. Reizis, Notch-RBP-J signaling controls the homeostasis of CD8- dendritic cells in the spleen. J. Exp. Med. 204, 1653–1664 (2007).
17
M. A. Travis, B. Reizis, A. C. Melton, E. Masteller, Q. Tang, J. M. Proctor, Y. Wang, X. Bernstein, X. Huang, L. F. Reichardt, J. A. Bluestone, D. Sheppard, Loss of integrin α(v)β8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).
18
M. Acharya, S. Mukhopadhyay, H. Païdassi, T. Jamil, C. Chow, S. Kissler, L. M. Stuart, R. O. Hynes, A. Lacy-Hulbert, αv Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice. J. Clin. Invest. 120, 4445–4452 (2010).
19
T. Gebhardt, P. G. Whitney, A. Zaid, L. K. Mackay, A. G. Brooks, W. R. Heath, F. R. Carbone, S. N. Mueller, Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).
20
S. Ariotti, J. B. Beltman, G. Chodaczek, M. E. Hoekstra, A. E. van Beek, R. Gomez-Eerland, L. Ritsma, J. van Rheenen, A. F. M. Marée, T. Zal, R. J. de Boer, J. B. A. G. Haanen, T. N. Schumacher, Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc. Natl. Acad. Sci. U.S.A. 109, 19739–19744 (2012).
21
A. J. Wagers, G. S. Kansas, Potent induction of alpha(1,3)-fucosyltransferase VII in activated CD4+ T cells by TGF-beta 1 through a p38 mitogen-activated protein kinase-dependent pathway. J. Immunol. 165, 5011–5016 (2000).
22
K. Hochweller, G. H. Wabnitz, Y. Samstag, J. Suffner, G. J. Hämmerling, N. Garbi, Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc. Natl. Acad. Sci. U.S.A. 107, 5931–5936 (2010).
23
J. M. Schenkel, K. A. Fraser, V. Vezys, D. Masopust, Sensing and alarm function of resident memory CD8+ T cells. Nat. Immunol. 14, 509–513 (2013).
24
Y. Ito, K. Miyazono, RUNX transcription factors as key targets of TGF-beta superfamily signaling. Curr. Opin. Genet. Dev. 13, 43–47 (2003).
25
L. K. Mackay, M. Minnich, N. A. M. Kragten, Y. Liao, B. Nota, C. Seillet, A. Zaid, K. Man, S. Preston, D. Freestone, A. Braun, E. Wynne-Jones, F. M. Behr, R. Stark, D. G. Pellicci, D. I. Godfrey, G. T. Belz, M. Pellegrini, T. Gebhardt, M. Busslinger, W. Shi, F. R. Carbone, R. A. W. van Lier, A. Kallies, K. P. J. M. van Gisbergen, Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).
26
B. B. McConnell, V. W. Yang, Mammalian Krüppel-like factors in health and diseases. Physiol. Rev. 90, 1337–1381 (2010).
27
N. Zhang, M. J. Bevan, TGF-β signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat. Immunol. 13, 667–673 (2012).
28
B. Grueter, M. Petter, T. Egawa, K. Laule-Kilian, C. J. Aldrian, A. Wuerch, Y. Ludwig, H. Fukuyama, H. Wardemann, R. Waldschuetz, T. Möröy, I. Taniuchi, V. Steimle, D. R. Littman, M. Ehlers, Runx3 regulates integrin alpha E/CD103 and CD4 expression during development of CD4-/CD8+ T cells. J. Immunol. 175, 1694–1705 (2005).
29
S. Sanjabi, M. M. Mosaheb, R. A. Flavell, Opposing effects of TGF-beta and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity 31, 131–144 (2009).
30
T. E. Boursalian, J. Golob, D. M. Soper, C. J. Cooper, P. J. Fink, Continued maturation of thymic emigrants in the periphery. Nat. Immunol. 5, 418–425 (2004).
31
J. G. Cyster, S. R. Schwab, Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30, 69–94 (2012).
32
P. De Togni, J. Goellner, N. H. Ruddle, P. R. Streeter, A. Fick, S. Mariathasan, S. C. Smith, R. Carlson, L. P. Shornick, J. Strauss-Schoenberger, et, Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994).
33
L. K. Mackay, A. T. Stock, J. Z. Ma, C. M. Jones, S. J. Kent, S. N. Mueller, W. R. Heath, F. R. Carbone, T. Gebhardt, Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation. Proc. Natl. Acad. Sci. U.S.A. 109, 7037–7042 (2012).
34
H. Shin, A. Iwasaki, A vaccine strategy that protects against genital herpes by establishing local memory T cells. Nature 491, 463–467 (2012).
35
S. Henri, D. Vremec, A. Kamath, J. Waithman, S. Williams, C. Benoist, K. Burnham, S. Saeland, E. Handman, K. Shortman, The dendritic cell populations of mouse lymph nodes. J. Immunol. 167, 741–748 (2001).
36
L. Ohl, M. Mohaupt, N. Czeloth, G. Hintzen, Z. Kiafard, J. Zwirner, T. Blankenstein, G. Henning, R. Förster, CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).
37
K. Takada, S. C. Jameson, Self-class I MHC molecules support survival of naive CD8 T cells, but depress their functional sensitivity through regulation of CD8 expression levels. J. Exp. Med. 206, 2253–2269 (2009).
38
L. M. Wakim, M. J. Bevan, Cross-dressed dendritic cells drive memory CD8+ T-cell activation after viral infection. Nature 471, 629–632 (2011).
39
B. Johansson-Lindbom, M. Svensson, M.-A. Wurbel, B. Malissen, G. Márquez, W. Agace, Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): Requirement for GALT dendritic cells and adjuvant. J. Exp. Med. 198, 963–969 (2003).
40
J. R. Mora, M. R. Bono, N. Manjunath, W. Weninger, L. L. Cavanagh, M. Rosemblatt, U. H. von Andrian, Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424, 88–93 (2003).
41
J. C. Dudda, J. C. Simon, S. Martin, Dendritic cell immunization route determines CD8+ T cell trafficking to inflamed skin: Role for tissue microenvironment and dendritic cells in establishment of T cell-homing subsets. J. Immunol. 172, 857–863 (2004).
42
V. R. Buchholz, T. N. M. Schumacher, D. H. Busch, T Cell Fate at the Single-Cell Level. Annu. Rev. Immunol. 34, 65–92 (2016).
43
N. L. Smith, R. K. Patel, A. Reynaldi, J. K. Grenier, J. Wang, N. B. Watson, K. Nzingha, K. J. Yee Mon, S. A. Peng, A. Grimson, M. P. Davenport, B. D. Rudd, Developmental Origin Governs CD8+ T Cell Fate Decisions during Infection. Cell 174, 117–130.e14 (2018).
44
R. B. Fulton, S. E. Hamilton, Y. Xing, J. A. Best, A. W. Goldrath, K. A. Hogquist, S. C. Jameson, The TCR’s sensitivity to self peptide-MHC dictates the ability of naive CD8(+) T cells to respond to foreign antigens. Nat. Immunol. 16, 107–117 (2015).
45
Y. Qin, B. S. Garrison, W. Ma, R. Wang, A. Jiang, J. Li, M. Mistry, R. T. Bronson, D. Santoro, C. Franco, D. A. Robinton, B. Stevens, D. J. Rossi, C. Lu, T. A. Springer, A Milieu Molecule for TGF-β Required for Microglia Function in the Nervous System. Cell 174, 156–171.e16 (2018).
46
H. Niwa, K. Yamamura, J. Miyazaki, Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193–199 (1991).
47
N. Goel, J. J. Docherty, M. M. Fu, D. H. Zimmerman, K. S. Rosenthal, A modification of the epidermal scarification model of herpes simplex virus infection to achieve a reproducible and uniform progression of disease. J. Virol. Methods 106, 153–158 (2002).
48
A. van Lint, M. Ayers, A. G. Brooks, R. M. Coles, W. R. Heath, F. R. Carbone, Herpes simplex virus-specific CD8+ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation. J. Immunol. 172, 392–397 (2004).
49
K.-T. C. Shade, B. Platzer, N. Washburn, V. Mani, Y. C. Bartsch, M. Conroy, J. D. Pagan, C. Bosques, T. R. Mempel, E. Fiebiger, R. M. Anthony, A single glycan on IgE is indispensable for initiation of anaphylaxis. J. Exp. Med. 212, 457–467 (2015).
50
M. Acharya, A. Sokolovska, J. M. Tam, K. L. Conway, C. Stefani, F. Raso, S. Mukhopadhyay, M. Feliu, E. Paul, J. Savill, R. O. Hynes, R. J. Xavier, J. M. Vyas, L. M. Stuart, A. Lacy-Hulbert, αv Integrins combine with LC3 and atg5 to regulate Toll-like receptor signalling in B cells. Nat. Commun. 7, 10917 (2016).
51
M. Schubert, S. Lindgreen, L. Orlando, AdapterRemoval v2: Rapid adapter trimming, identification, and read merging. BMC Res. Notes 9, 88 (2016).
52
B. Langmead, S. L. Salzberg, Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
53
S. Heinz, C. Benner, N. Spann, E. Bertolino, Y. C. Lin, P. Laslo, J. X. Cheng, C. Murre, H. Singh, C. K. Glass, Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol. Cell 38, 576–589 (2010).
54
A. R. Quinlan, I. M. Hall, BEDTools: A flexible suite of utilities for comparing genomic features. Bioinformatics 26, 841–842 (2010).
55
S. Anders, W. Huber, Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010).
56
F. Ramírez, F. Dündar, S. Diehl, B. A. Grüning, T. Manke, deepTools: A flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 42, W187–W191 (2014).
57
C. Y. McLean, D. Bristor, M. Hiller, S. L. Clarke, B. T. Schaar, C. B. Lowe, A. M. Wenger, G. Bejerano, GREAT improves functional interpretation of cis-regulatory regions. Nat. Biotechnol. 28, 495–501 (2010).

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Science
Volume 366 | Issue 6462
11 October 2019

Submission history

Received: 28 September 2018
Accepted: 4 September 2019
Published in print: 11 October 2019

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Acknowledgments

We thank S. Pillai, A. Wagers, U. von Andrian, S. Beyaz, and N. Giovannone for helpful discussions and critical feedback on the manuscript. Funding: This work was supported by the Bob and Laura Reynolds MGH Research Scholar Award and NIH grants R21 AR070981 (to T.R.M), R01 AI040618 (to A.L), T32 CA207201 (to V.M.), T32 AR007258 (to E.C.), R01 AI121546 (to S.K.B.), and R01 AI107087 (to K.L.J). The Wellcome Centre for Cell-Matrix Research, University of Manchester, is supported by core funding from the Wellcome Trust (grant no. 203128/Z/16/Z). Author contributions: V.M., S.K.B., E.C., R.D.W., R.M.-B., F.M., A.L., J.W.G., R.A.R., C.P.M., M.H, D.R.S., T.A., and A.Y.C. performed experiments; V.M. analyzed the data; A.L.-H. and M.A.T generated mice; A.L.-H., K.L.J., and A.D.L. made important conceptual contributions; and V.M. and T.R.M. designed the experiments and wrote the manuscript. Competing interests: The authors declare no competing interests. Data and materials availability: ATAC-seq data are available under GEO accession number GSE133504. All other data needed to evaluate the conclusions in this paper are available in the main text or the supplementary materials.

Authors

Affiliations

Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Immunology Graduate Program, Harvard Medical School, Boston, MA, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Center for Computational Biology, Flatiron Institute, New York, NY, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Esteban Carrizosa
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Bluebird Bio, 60 Binney Street, Cambridge, MA 02142, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Immunology Graduate Program, Harvard Medical School, Boston, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Benaroya Research Institute, Seattle, WA, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Lydia Becker Institute of Immunology and Inflammation, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Harvard Medical School, Boston, MA, USA.
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Present Address: University of California Irvine, Irvine, CA 92697, USA.
Mark A. Travis
Lydia Becker Institute of Immunology and Inflammation, Wellcome Trust Centre for Cell-Matrix Research, Faculty of Biology, Medicine and Health Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
Adam Lacy-Hulbert
Benaroya Research Institute, Seattle, WA, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.

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Notes

†Corresponding author. Email: [email protected]

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