T cell differentiation in the thymus is dependent on signaling by both T cell antigen receptors and by cytokine receptors. Our current understanding of how lineage choice is determined in the thymus is built around the concept that signaling by the T cell antigen receptor prevents signaling by cytokine receptors, and that cytokine signaling only occurs after signaling by the T cell antigen receptor has ceased. Despite its central role in T cell development, it is not known how T cell antigen receptor signaling 'desensitizes'the cytokine receptor so that it is no longer able to transmit signals into the cell. Consequently, we have undertaken a systematic examination of the molecular basis by which cytokine receptor signaling is impaired by TCR signals in developing T cells in the thymus and in mature T cells in the periphery.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011117-05
Application #
8552992
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$357,064
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Pobezinsky, Leonid A; Etzensperger, Ruth; Jeurling, Susanna et al. (2015) Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function. Nat Immunol 16:517-24
Takada, Kensuke; Van Laethem, Francois; Xing, Yan et al. (2015) TCR affinity for thymoproteasome-dependent positively selecting peptides conditions antigen responsiveness in CD8(+) T cells. Nat Immunol 16:1069-76
Tai, Xuguang; Erman, Batu; Alag, Amala et al. (2013) Foxp3 Transcription Factor Is Proapoptotic and Lethal to Developing Regulatory T Cells unless Counterbalanced by Cytokine Survival Signals. Immunity :
Kimura, Motoko Y; Pobezinsky, Leonid A; Guinter, Terry I et al. (2013) IL-7 signaling must be intermittent, not continuous, during CD8? T cell homeostasis to promote cell survival instead of cell death. Nat Immunol 14:143-51
Adoro, Stanley; McCaughtry, Thomas; Erman, Batu et al. (2012) Coreceptor gene imprinting governs thymocyte lineage fate. EMBO J 31:366-77
McCaughtry, Tom M; Etzensperger, Ruth; Alag, Amala et al. (2012) Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus. J Exp Med 209:2263-76
Tai, Xuguang; Van Laethem, Francois; Pobezinsky, Leonid et al. (2012) Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells. Blood 119:5155-63
Adoro, Stanley; Park, Jung-Hyun; Singer, Alfred (2012) Coreceptor gene ""imprinting:"" a genetic solution to a developmental dilemma in T cells. Cell Cycle 11:833-4
Tikhonova, Anastasia N; Van Laethem, Fran├žois; Hanada, Ken-ichi et al. (2012) ?? T cell receptors that do not undergo major histocompatibility complex-specific thymic selection possess antibody-like recognition specificities. Immunity 36:79-91
Van Laethem, Fran├žois; Tikhonova, Anastasia N; Singer, Alfred (2012) MHC restriction is imposed on a diverse T cell receptor repertoire by CD4 and CD8 co-receptors during thymic selection. Trends Immunol 33:437-41

Showing the most recent 10 out of 12 publications