Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011117-03
Application #
8157641
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2010
Total Cost
$390,496
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

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
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
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 38:1116-28
Tikhonova, Anastasia N; Van Laethem, François; 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, François; 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
Adoro, Stanley; McCaughtry, Thomas; Erman, Batu et al. (2012) Coreceptor gene imprinting governs thymocyte lineage fate. EMBO J 31:366-77
Gegonne, Anne; Tai, Xuguang; Zhang, Jinghui et al. (2012) The general transcription factor TAF7 is essential for embryonic development but not essential for the survival or differentiation of mature T cells. Mol Cell Biol 32:1984-97
Pobezinsky, Leonid A; Angelov, Georgi S; Tai, Xuguang et al. (2012) Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat Immunol 13:569-78
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

Showing the most recent 10 out of 12 publications