T-cell homeostasis is critical for the adaptive immune system to respond to a variety of new pathogens and for maintaining immunological memory. It contributes to the recovery of the peripheral T-cell pool after T cell depletion caused by irradiation or viral infection. In cancer patients, homeostatic expansion of tumor-specific T cells following adoptive T cell therapy in lymphopenic cancer patients induced by chemo or radiotherapy may be beneficial for the patients to control and eliminate cancers. In HIV-infected subjects, impairment of homeostatic proliferation causes severe depletion of CD4 + T cells and disease progression to AIDS. Thymic stromal lymphopoietin (TSLP) is an IL-7-1ike cytokine. We have recently demonstrated that human TSLP strongly activated CD11c+ immature myeloid DCs (TSLP-DC). TSLP-DCs induced a strong allogeneic naive CD4+ T cell proliferation and subsequent differentiation into inflammatory TH2 cells. More recently, we found that TSLP was expressed by epithelial cells of thymus and of tonsils in the absence of allergic inflammation, suggesting that human TSLP might have additional functions. We found that TSLP activated DCs could induce a robust homeostatic proliferation of autologous naive CD4+ T cells in the absence of exogenous antigens and cytokines. This finding suggests that TSLP expressed by epithelial cells in thymus and peripheral lymphoid tissues may play a critical role in DC-mediated T cell homeostasis. The objectives of this proposal are: i) to characterize homeostatic proliferation of human naive CD4+ T cells induced by autologous TSLP-activated DCs; ii) to elucidate the molecular mechanisms underlying the ability of TSLP-activated DCs to induce homeostatic T cell proliferation; and iii) to understand why TSLP-activated DCs induce inflammatory TH2 differentiation in the allogeneic system, but homeostatic T cell proliferation in the autologous system.
The specific aims i n this proposal determining the function of DCs and hTSLP in the regulation of human peripheral T cell homeostasis may provide new strategies in enhancing immune responses to infectious diseases and cancer, and in controlling autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI062888-03
Application #
7150613
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Gondre-Lewis, Timothy A
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
3
Fiscal Year
2007
Total Cost
$391,102
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Ito, Tomoki; Liu, Yong-Jun; Arima, Kazuhiko (2012) Cellular and molecular mechanisms of TSLP function in human allergic disorders--TSLP programs the ""Th2 code"" in dendritic cells. Allergol Int 61:35-43
Hanabuchi, Shino; Ito, Tomoki; Park, Woon-Ryon et al. (2010) Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J Immunol 184:2999-3007
Román, Eulogia; Shino, Hanabuchi; Qin, F Xiao-Feng et al. (2010) Cutting edge: Hematopoietic-derived APCs select regulatory T cells in thymus. J Immunol 185:3819-23
Lu, Ning; Wang, Yi-Hong; Wang, Yui-Hsi et al. (2009) TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis. J Exp Med 206:2111-9
Ito, Tomoki; Hanabuchi, Shino; Wang, Yi-Hong et al. (2008) Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 28:870-80