Nave CD8 T cells require both IL-7 signaling and TCR signaling through the interaction with self peptides and MHC complex for T cell homeostasis. However nobody knows why these cells require two signals or why IL-7 signaling is not enough, since IL-7 signaling by itself can provide strong survival signals. Because IL-7 signaling can down-regulate IL-7R expression, we hypothesizes that down-regulation of IL-7R causes a problem for nave CD8 T cell homeostasis and survival. To address this question, we used T cells expressing transgenic IL-7R under the control of the human CD2 promoter which is not down-regulated by IL-7 stimulation. We found that IL-7R Tg nave CD8 T cells can proliferate dramatically in vitro in response to IL-7. This suggests that the maintenance of IL-7Ra expression is important for the proliferation by IL-7. HY TCR Tg female T cells cannot undergo homeostatic proliferation because their TCR affinity to self ligand is too low. We found that their IL-7R expression is very low and can be up-regulated by stronger TCR signaling. Interestingly, introducing an IL-7Ra Tg to HY T cells rescued their homeostatic proliferation. Consequently, we have discovered a new mechanism of T cell homeostasis in which homeostatic TCR signaling mediates the maintenance of IL-7R expression.

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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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; 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

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