The human thymus is required for the generation, maturation, and export of T lymphocytes to the periphery where they coordinate adaptive immune responses. Naive T cells are generated via thymopoiesis in early childhood followed by a gradual reduction in thymic function and an age-dependent involution of the functional organ volume beginning in puberty. It is not understood how and whether human naive T cells are maintained in the context of decreasing thymic output throughout life, mainly because studies on human T cell development have been limited to the sampling of peripheral blood. The issue of naive T cell survival and the role of thymic output in repopulation of T cells is of particular relevance in understanding the preservation of an effective immune response in aging individuals. With increasing age, size of the naive T cell pool is affected both by a decrease in thymic export and a transition into effector memory cells following exposure to antigen. We propose here a new approach to study the dynamics of human T cell development and homeostasis by investigating T cell populations in primary and secondary lymphoid tissue isolated from individual organ donors. Results from the proposed study will have implications not only in the field of immunology which pertains to aging but will provide new information of how naive T cells are distributed and maintained in tissues not previously characterized. Furthermore the proposed research will be of relevance to promoting immune responses to new pathogens or vaccines while furthering the understanding of mechanisms for immune dysregulations that can occur with advancing age.

Public Health Relevance

The proposed research will conduct novel studies of human immune cells in tissue sites throughout the body that have not previously been characterized, using a unique tissue resource set up by the research advisor. The results to be obtained and concepts to be learned will yield significant advances in human immunology of aging populations and impact the way we analyze and interpret disease pathologies, design vaccines, and use immunotherapy to treat and cure intractable diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG047003-02
Application #
8742565
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fuldner, Rebecca A
Project Start
2013-09-16
Project End
2016-09-15
Budget Start
2014-09-16
Budget End
2015-09-15
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
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Thome, Joseph J C; Bickham, Kara L; Ohmura, Yoshiaki et al. (2016) Early-life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues. Nat Med 22:72-7
Zuber, Julien; Shonts, Brittany; Lau, Sai-Ping et al. (2016) Bidirectional intragraft alloreactivity drives the repopulation of human intestinal allografts and correlates with clinical outcome. Sci Immunol 1:
Thome, Joseph J C; Grinshpun, Boris; Kumar, Brahma V et al. (2016) Longterm maintenance of human naive T cells throughin situhomeostasis in lymphoid tissue sites. Sci Immunol 1:
Brestoff, Jonathan R; Kim, Brian S; Saenz, Steven A et al. (2015) Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519:242-6
Thome, Joseph J C; Farber, Donna L (2015) Emerging concepts in tissue-resident T cells: lessons from humans. Trends Immunol 36:428-35
Wojno, E D Tait; Monticelli, L A; Tran, S V et al. (2015) The prostaglandin D? receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung. Mucosal Immunol 8:1313-23
Thome, Joseph J C; Yudanin, Naomi; Ohmura, Yoshiaki et al. (2014) Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159:814-28
Subramanian, Manikandan; Hayes, Crystal D; Thome, Joseph J et al. (2014) An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo. J Clin Invest 124:1296-308

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