The discovery of T resident memory (TRM) cells in skin and other epithelial tissues has revolutionized our understanding of protective T cell memory. While we are delighted that our long standing R01 grant has contributed to the discovery TRM in humans, and the initial characterization skin TRM in mouse models of viral infection, these important cells remain poorly understood. We do know that TRM in skin provide much more rapid and potent protection against re-infection with pathogenic virus, and that TRM tend to not re-circulate from skin to blood. VACV skin infection results in the seeding of antigen specific TRM most effectively to infected skin, slightly less effectively to distant skin, and leas effectively (but still significantly) to other epithelial organs that interface the environment (e.., lung). Taken together, our murine and human data provoke us to make two related hypotheses: first, that these TRM are the most important T cells with regard to protective immune memory in general, and second, that their dysfunctional activation in man underlies most T cell mediated diseases of peripheral tissues, including skin (psoriasis), lung (asthma), gut (IBD), joint (RA), and CNS (MS). If these hypotheses are correct, then a better understanding of the fundamental biology of these TRM is central to our understanding of how to diagnose and more effectively treat a broad spectrum of human diseases, as well as to configure means to enhance protective immunity against pathogens. Using T cell receptor deep sequencing, we have made the unexpected observation that every TRM in tissue has a clonal counterpart in the lymph node TCM compartment, strongly arguing that TRM and TCM arise from a common naive T cell precursor. Thus, it is not antigen specificity per se, but rather their anatomic location that make TRM superior to TCM in terms of rapid protective immunity. The interplay between TRM and TCM, and the recruitment of existing TCM to become new TRM upon subsequent antigen challenge is also a focus of this grant. To broader our vantage point, we will use three distinct models of skin immune responses: contact hypersensitivity (CHS), vaccinia virus (VACV) infection, and C.albicans infection, coupled with genetically engineered mice, novel imaging approaches, and deep sequencing of the TCR, to try to better understand how TRM are generated and maintained, and what role they play in the maintenance of immune memory in viral, extracellular pathogen, and environmental antigen driven diseases. This grant is highly significant to human disease, uses innovative approaches and is based on novel technology, proposes ambitious but feasible approaches to be performed by experienced investigators in a supportive environment, and fervently hope it can be funded.

Public Health Relevance

The discovery of a very important population of protective memory T cells that reside the skin and other tissues that interface our environment is quite recent. Work proposed in this grant application will greatly increase our understanding of the biology of these important cells in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR065807-17
Application #
8738407
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
1997-09-08
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Jain, Salvia; Stroopinsky, Dina; Yin, Li et al. (2015) Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma. Blood 126:354-62
Park, Chang Ook; Kupper, Thomas S (2015) The emerging role of resident memory T cells in protective immunity and inflammatory disease. Nat Med 21:688-97
Gaide, Olivier; Emerson, Ryan O; Jiang, Xiaodong et al. (2015) Common clonal origin of central and resident memory T cells following skin immunization. Nat Med 21:647-53
Guenova, Emmanuella; Skabytska, Yuliya; Hoetzenecker, Wolfram et al. (2015) IL-4 abrogates T(H)17 cell-mediated inflammation by selective silencing of IL-23 in antigen-presenting cells. Proc Natl Acad Sci U S A 112:2163-8
Watanabe, Rei; Gehad, Ahmed; Yang, Chao et al. (2015) Human skin is protected by four functionally and phenotypically discrete populations of resident and recirculating memory T cells. Sci Transl Med 7:279ra39
Seneschal, Julien; Jiang, Xiaodong; Kupper, Thomas S (2014) Langerin+ dermal DC, but not Langerhans cells, are required for effective CD8-mediated immune responses after skin scarification with vaccinia virus. J Invest Dermatol 134:686-94
Watanabe, Rei; Teague, Jessica E; Fisher, David C et al. (2014) Alemtuzumab therapy for leukemic cutaneous T-cell lymphoma: diffuse erythema as a positive predictor of complete remission. JAMA Dermatol 150:776-9
Jiang, Xiaodong; Clark, Rachael A; Liu, Luzheng et al. (2012) Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity. Nature 483:227-31
Purwar, Rahul; Schlapbach, Christoph; Xiao, Sheng et al. (2012) Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med 18:1248-53
Tian, Tian; Dubin, Krista; Jin, Qiushuang et al. (2012) Disruption of TNF-α/TNFR1 function in resident skin cells impairs host immune response against cutaneous vaccinia virus infection. J Invest Dermatol 132:1425-34

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