The conventional view on T cell development posits that signals from the same T cell receptor (TCR) determines both positive and negative selection as well as lineage choice into mature CD4+ helper and CD8+ cytotoxic cells. The precise mechanism how this is achieved is still under dispute but it has been proposed that either quantitative or qualitative differences in TCR signaling would account for the different outcomes of lineage choice. In contrast to such views, here we show that TCR signaling alone is not sufficient to determine cell fate of developing thymocytes, and that CD4/CD8 lineage choice requires additional cues by cytokines such as interleukin-7 (IL-7). Using conditional deletion of immediate downstream signaling molecules of the IL-7 receptor, we demonstrate that IL-7 induced cytokine signals are required for CD8 lineage choice and for the differentiation into mature CD8+ cytotoxic T cells in vivo. Our data establish a previously unappreciated role for in vivo IL-7 and other gamma c-cytokines in CD8 lineage commitment of immature thymocytes, which is consistent with the kinetic signaling model of T cell lineage choice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011111-04
Application #
8349333
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2011
Total Cost
$390,914
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Gegonne, Anne; Chen, Qing-Rong; Dey, Anup et al. (2018) Immature CD8 Single-Positive Thymocytes Are a Molecularly Distinct Subpopulation, Selectively Dependent on BRD4 for Their Differentiation. Cell Rep 24:117-129
Madi, Asaf; Poran, Asaf; Shifrut, Eric et al. (2017) T cell receptor repertoires of mice and humans are clustered in similarity networks around conserved public CDR3 sequences. Elife 6:
Etzensperger, Ruth; Kadakia, Tejas; Tai, Xuguang et al. (2017) Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus. Nat Immunol 18:1218-1227
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Tai, Xuguang; Singer, Alfred (2014) Basis of Treg development in the thymus. Cell Cycle 13:501-2
Van Laethem, Fran├žois; 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

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