The thymus produces MHC-restricted abT cells that only recognize antigenic ligands in association with MHC or MHC-like molecules. We hypothesized that CD4 and CD8 coreceptors might be impose MHC-specificity on a broader abTCR repertoire during thymic selection because they bind and effectively sequester the tyrosine kinase Lck, thereby preventing TCR signaling by non-MHC ligands that do not engage either coreceptor. Using mice deficient for both CD4 and CD8 as well as MHC (Quad-deficient), we discoverd that ab thymocytes can be signaled by non-MHC ligands in the absence of coreceptors in vivo. In addition, we tested the critical role of coreceptors by introducing CD4 transgenes into Quad-deficient mice. Whereas sequestration of Lck by wild-type CD4 blocked signaling by non-MHC ligands on ab thymocytes, introducing a tailless form of CD4 didnt. We conclude that in the absence of Lck sequestration by coreceptors, thymocytes can be signaled by non-MHC ligands. Therefore, CD4 and CD8 impose MHC-specificity on a broad abTCR repertoire by preventing thymocytes to be selected by non-MHC ligands.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Cancer Institute Division of Basic Sciences
Zip Code
Tai, Xuguang; Singer, Alfred (2014) Basis of Treg development in the thymus. Cell Cycle 13:501-2
Van Laethem, François; Tikhonova, Anastasia N; Pobezinsky, Leonid A et al. (2013) Lck availability during thymic selection determines the recognition specificity of the T cell repertoire. Cell 154:1326-41
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
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, 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

Showing the most recent 10 out of 12 publications