The immune system controls the numbers as well as the activation status of the lymphocytes by an active mechanism of homeostatic regulation. Following transfer into lymphopenic conditions, T cells undergo proliferation to compensate lymphocyte deficiency, while T cells remain quiescent after transfer into lymphocyte sufficient hosts. Underlying mechanisms of how such proliferation is induced and regulated are not well understood. We have previously demonstrated heterogeneity of T cell proliferation under lymphopenic conditions: IL-7-dependent slow proliferation and IL-7-independent fast proliferation (referred to as "endogenous proliferation"). Furthermore, endogenous proliferation is found closely associated with differentiation into memory phenotype cells, suggesting that different mechanism appears to be involved in endogenous proliferation. From preliminary studies we found that: 1) initial accumulation of T cells that undergo endogenous proliferation is found mainly in the spleen but not in the mesenteric lymph nodes;2) depletion of gut flora by antibiotic treatment has little effect on endogenous proliferation;3) endogenous proliferation of naive T cells is mainly controlled by the presence of memory T cells;4) repertoire complexity but not total numbers of the memory T cells plays a key role in limiting the endogenous proliferation;5) memory CD4 T cells suppress endogenous proliferation of both naive CD4 and CD8 T cells, while memory CD8 T cells only suppress endogenous proliferation of naive CD8 T cells;6) memory T cells compete with each other, not only to maintain their pool size but also to maximize the repertoire complexity. We hypothesize that endogenous T cell proliferation, triggered by self-antigens expressed on DCs generates a diverse repertoire of memory T cells. These memory cells alter DC functions, further regulating subsequent naive T cell proliferation.
Three specific aims are proposed in order to test the hypothesis.
Aim #1 will determine if DCs are required for the induction of endogenous proliferation in lymphopenic hosts.
Aim #2 will define cellular mechanisms mediating memory T cell inhibition of naive T cell endogenous proliferation.
Aim #3 will experiments is expected to provide important insights into understanding homeostatic regulation of peripheral T cells. The studies are clinically relevant to establish strategies to avoid dysregulated lymphocyte homeostasis, often found in autoimmunity or therapeutic immunoablation. define the contribution of apoptosis to memory cell homeostasis. Completion of the proposed

Public Health Relevance

Summary The immune system evolves an active process of homeostatic control mechanism that ensures its diversity and functionality. Homeostatic dysregulation is believed to link to the development of multiple disorders, including immunodeficiency, autoimmunity and a failure of solid organ transplantation. The current proposal aims to investigate underlying cellular mechanism, and the results will aid our understanding of the immune mechanism and facilitate therapeutic strategies to treat disorders caused by the dysregulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI074932-04
Application #
8197068
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
2008-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$384,689
Indirect Cost
$139,664
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Visperas, A; Do, J S; Bulek, K et al. (2014) IL-27, targeting antigen-presenting cells, promotes Th17 differentiation and colitis in mice. Mucosal Immunol 7:625-33
Do, Jeong-su; Asosingh, Kewal; Baldwin 3rd, William M et al. (2014) Cutting edge: IFN-?R signaling in non-T cell targets regulates T cell-mediated intestinal inflammation through multiple mechanisms. J Immunol 192:2537-41
Do, Jeong-Su; Visperas, Anabelle; Freeman, Michael L et al. (2014) Colitogenic effector T cells: roles of gut-homing integrin, gut antigen specificity and ýýýý T cells. Immunol Cell Biol 92:90-8
Do, Jeong-su; Baldwin 3rd, William M; Min, Booki (2014) Spontaneous proliferation of H2M-/- CD4 T cells results in unusual acute hepatocellular necrosis. PLoS One 9:e110516
Visperas, Anabelle; Shen, Bo; Min, Booki (2014) ?? T cells restrain extrathymic development of Foxp3+-inducible regulatory T cells via IFN-?. Eur J Immunol 44:2448-56
Visperas, Anabelle; Do, Jeongsu; Min, Booki (2014) Cellular factors targeting APCs to modulate adaptive T cell immunity. J Immunol Res 2014:750374
Do, Jeong-su; Foucras, Gilles; Kamada, Nobuhiko et al. (2012) Both exogenous commensal and endogenous self antigens stimulate T cell proliferation under lymphopenic conditions. Cell Immunol 272:117-23
Do, Jeong-Su; Visperas, Anabelle; Oh, Keunhee et al. (2012) Memory CD4 T cells induce selective expression of IL-27 in CD8+ dendritic cells and regulate homeostatic naive T cell proliferation. J Immunol 188:230-7
Do, Jeong-su; Visperas, Anabelle; Dong, Chen et al. (2011) Cutting edge: Generation of colitogenic Th17 CD4 T cells is enhanced by IL-17+ ?? T cells. J Immunol 186:4546-50
Do, Jeong-su; Fink, Pamela J; Li, Lily et al. (2010) Cutting edge: spontaneous development of IL-17-producing gamma delta T cells in the thymus occurs via a TGF-beta 1-dependent mechanism. J Immunol 184:1675-9

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