The broad objective of this project are to study the stimuli that induce tolerance in normal T cells and in vivo, with emphasis on the roles of costimulators, antigen-presenting cells and cytokines, and to examine the tolerance sensitivity of different T cell populations, including cells that escape negative selection in the thymus. A major emphasis is on the use of T cell receptor (TCR) transgenic mice.
The specific aims of the project are the following. 1. Tolerance in naive CD4+ T cells in vitro The development of tolerance will be studied in normal CD4+ T cells isolated from transgenic mice expressing a TCR specific for cytochrome c + I-Ek. The types of APCs that induce tolerance, and their costimulators, will be examined. The ability of cytokines to prevent tolerance will be studied. The functional impairment and fate of tolerant cells will be examined. 2. Mechanisms of tolerance induction in vivo Peripheral T cell tolerance will be induced in normal and TCR transgenic mice by high-dose aqueous antigen, antigen targeted to B cells, and oral antigen administration. The influence of cytokines on T cell tolerance will be examined with specific antagonists. The role of B cells as tolerogenic APCs will be studied in B-deficient mice. Thus, the is project addresses fundamental questions about the induction and maintenance of peripheral T cell tolerance in normal T cells and in vivo, and the physiologic significance of peripheral tolerance.

Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Proekt, Irina; Miller, Corey N; Lionakis, Michail S et al. (2017) Insights into immune tolerance from AIRE deficiency. Curr Opin Immunol 49:71-78
Sanchez Rodriguez, Robert; Pauli, Mariela L; Neuhaus, Isaac M et al. (2014) Memory regulatory T cells reside in human skin. J Clin Invest 124:1027-36
Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel et al. (2014) Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med 6:258ra142
Stumpf, Melanie; Zhou, Xuyu; Chikuma, Shunsuke et al. (2014) Tyrosine 201 of the cytoplasmic tail of CTLA-4 critically affects T regulatory cell suppressive function. Eur J Immunol 44:1737-46
Bailey-Bucktrout, Samantha L; Martinez-Llordella, Marc; Zhou, Xuyu et al. (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39:949-62
Zikherman, Julie; Parameswaran, Ramya; Hermiston, Michelle et al. (2013) The structural wedge domain of the receptor-like tyrosine phosphatase CD45 enforces B cell tolerance by regulating substrate specificity. J Immunol 190:2527-35
Jeker, Lukas T; Bluestone, Jeffrey A (2013) MicroRNA regulation of T-cell differentiation and function. Immunol Rev 253:65-81
de Kouchkovsky, Dimitri; Esensten, Jonathan H; Rosenthal, Wendy L et al. (2013) microRNA-17-92 regulates IL-10 production by regulatory T cells and control of experimental autoimmune encephalomyelitis. J Immunol 191:1594-605
Gratz, Iris K; Truong, Hong-An; Yang, Sara Hsin-Yi et al. (2013) Cutting Edge: memory regulatory t cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J Immunol 190:4483-7
Baumjohann, Dirk; Kageyama, Robin; Clingan, Jonathan M et al. (2013) The microRNA cluster miR-17?92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat Immunol 14:840-8

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