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Signaling thresholds govern heterogeneity in IL‐7‐receptor‐mediated responses of naïve CD8 + T cells
Author(s) -
Palmer Megan J,
Mahajan Vinay S,
Chen Jianzhu,
Irvine Darrell J,
Lauffenburger Douglas A
Publication year - 2011
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1038/icb.2011.5
Subject(s) - cd5 , t cell receptor , microbiology and biotechnology , cd8 , biology , cytotoxic t cell , interleukin 7 receptor , receptor , t cell , il 2 receptor , immune system , antigen , immunology , in vitro , genetics
Variable sensitivity to T‐cell‐receptor (TCR)‐ and IL‐7‐receptor (IL‐7R)‐mediated homeostatic signals among naïve T cells has thus far been largely attributed to differences in TCR specificity. We show here that even when withdrawn from self‐peptide‐induced TCR stimulation, CD8 + T cells exhibit heterogeneous responses to interleukin‐7 (IL‐7) that are mechanistically associated with IL‐7R expression differences that correlate with relative CD5 expression. Whereas CD5 hi and CD5 lo T cells survive equivalently in the presence of saturating IL‐7 levels in vitro , CD5 hi T cells proliferate more robustly. Conversely, CD5 lo T cells exhibit prolonged survival when withdrawn from homeostatic stimuli. Through quantitative experimental analysis of signaling downstream of IL‐7R, we find that the enhanced IL‐7 responsiveness of CD5 hi T cells is directly related to their greater surface IL‐7R expression. Further, we identify a quantitative threshold in IL‐7R‐mediated signaling capacity required for proliferation that lies well above an analogous threshold requirement for survival. These distinct thresholds allow subtle differences in IL‐7R expression between CD5 lo and CD5 hi T cells to give rise to significant variations in their respective IL‐7‐induced proliferation, without altering survival. Heterogeneous IL‐7 responsiveness is observed similarly in vivo , with CD5 hi naïve T cells proliferating preferentially in lymphopenic mice or lymphoreplete mice administered with exogenous IL‐7. However, IL‐7 in lymphoreplete mice appears to be maintained at an effective level for preserving homeostasis, such that neither CD5 hi IL‐7R hi nor CD5 lo IL‐7R lo T cells proliferate or survive preferentially. Our findings indicate that IL‐7R‐mediated signaling not only maintains the size but also impacts the diversity of the naïve T‐cell repertoire.