Since 1998, this grant has funded a body of work on skin immunology that most recently has focused on ?skin resident? memory T cells, or TRM. Our work with Vaccinia virus (VACV) taught us a great deal about the biology of CD8 TRM, and their critical role in host defense against viral infection in peripheral tissues. While the VACV work elucidated CD8 TRM biology, more recent work has helped define the behavior and function of skin CD4 TRM. Additional work has contributed to understanding the lineage development of TRM, and showed that TRM and TCM derive from a common nave T cell precursor. The corollary to this observation is that every TRM clone in peripheral tissue is mirrored by a TCR identical TCM clone in peripheral blood/secondary lymphoid tissue, suggesting that there are two compartments of adaptive immune memory?one in tissue, which is ?backed up? in secondary lymphoid tissue. While the benefit of TRM is the maintenance of superior host defense in peripheral tissues, there is a ?dark side? to TRM. Growing evidence suggests that pathogenic TRM mediate tissue-specific immune-mediated diseases as diverse as psoriasis and vitiligo, asthma, inflammatory bowel disease, rheumatoid and spondylo-arthritis, and insulin-dependent diabetes. We hypothesize that the difficulty in achieving durable remission in these diseases is because the genetic program of TRM is focused on maintaining their indefinite survival in tissues. While TRM?s disease-causing activity can be transiently blocked with immune suppressive drugs, there is currently no means of dislodging these pathogenic cells from tissue. As a result, these diseases are chronic and relapsing. In 2017, we reported that CD8 TRM in skin depend upon uptake of exogenous free fatty acids (FFA), which they use for mitochondrial ? oxidation and ATP generation. If either free fatty acid uptake or mitochondrial ? oxidation are blocked, CD8 TRM do not survive in peripheral tissue. We believe that blocking TRM lipid uptake and metabolism may dislodge pathogenic TRM from tissue, which is the overarching premise of this proposal. Accordingly, we seek to more fully characterize the evolution of TRM in tissue at the single cell level, extend and better characterize the dependence of CD8 TRM on exogenous lipid and lipid metabolism, test the lipid dependence of CD4 TRM , and test the hypothesis that blocking TRM lipid uptake and metabolism can dislodge them from tissue. This may forge a path towards more durable treatment of TRM-mediated disorders of skin and other tissues.

Public Health Relevance

Resident memory T cells in skin are important for host defense against infection. Recently, these cells have been implicated in inflammatory skin diseases. This proposal seeks to develop methods of dislodging these resident memory cells from skin as a potential treatment for such skin diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR065807-21
Application #
9594926
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
1997-09-08
Project End
2023-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
21
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
Park, Chang Ook; Fu, Xiujun; Jiang, Xiaodong et al. (2018) Staged development of long-lived T-cell receptor ?? TH17 resident memory T-cell population to Candida albicans after skin infection. J Allergy Clin Immunol 142:647-662
Pan, Youdong; Kupper, Thomas S (2018) Metabolic Reprogramming and Longevity of Tissue-Resident Memory T Cells. Front Immunol 9:1347
Jiang, Xiaodong; Park, Chang Ook; Geddes Sweeney, Jenna et al. (2017) Dermal ?? T Cells Do Not Freely Re-Circulate Out of Skin and Produce IL-17 to Promote Neutrophil Infiltration during Primary Contact Hypersensitivity. PLoS One 12:e0169397
Pan, Youdong; Tian, Tian; Park, Chang Ook et al. (2017) Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543:252-256
Collins, Nicholas; Jiang, Xiaodong; Zaid, Ali et al. (2016) Skin CD4(+) memory T cells exhibit combined cluster-mediated retention and equilibration with the circulation. Nat Commun 7:11514
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
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
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
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

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