Signaling thresholds govern heterogeneity in XXXX -mediated responses of na  ve CD8(+) T cells.

@entity6689 @entity19 @entity15592 @entity10191
Variable sensitivity to T-cell-receptor (TCR)- and @entity15592 ( @entity15592 )-mediated homeostatic signals among na  ve 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 We show here that even when withdrawn from self-peptide-induced TCR stimulation, CD8(+) T cells exhibit heterogeneous responses to @entity10191 ( @entity10191 ) that are mechanistically associated with @entity15592 expression differences that correlate with relative @entity6689 expression. Whereas @entity6689 (hi) and @entity6689 (lo) T cells survive equivalently in the presence of saturating @entity10191 levels in vitro, @entity6689 (hi) T cells proliferate more robustly. Conversely, @entity6689 (lo) T cells exhibit prolonged survival when withdrawn from homeostatic stimuli. Through quantitative experimental analysis of signaling downstream of @entity15592 , we find that the enhanced @entity10191 responsiveness of @entity6689 (hi) T cells is directly related to their greater surface @entity15592 expression. Further, we identify a quantitative threshold in @entity15592 -mediated signaling capacity required for proliferation that lies well above an analogous threshold requirement for survival. These distinct thresholds allow subtle differences in @entity15592 expression between @entity6689 (lo) and @entity6689 (hi) T cells to give rise to significant variations in their respective @entity10191 -induced proliferation, without altering survival. Heterogeneous @entity10191 responsiveness is observed similarly in vivo, with @entity6689 (hi) na  ve T cells proliferating preferentially in lymphopenic @entity19 or lymphoreplete @entity19 administered with exogenous @entity10191 . However, @entity10191 in lymphoreplete @entity19 appears to be maintained at an effective level for preserving homeostasis, such that neither @entity6689 (hi) @entity15592 (hi) nor @entity6689 (lo) @entity15592 (lo) T cells proliferate or survive preferentially. Our findings indicate that @entity15592 -mediated signaling not only maintains the size but also impacts the diversity of the na  ve T-cell repertoire.
