Signaling thresholds govern heterogeneity in IL‐7‐receptor‐mediated responses of naïve CD8+ T cells

• Published in: Immunology and cell biology 2011-07, Vol.89 (5), p.581-594
• Main Authors: Palmer, Megan J, Mahajan, Vinay S, Chen, Jianzhu, Irvine, Darrell J, Lauffenburger, Douglas A
• Format: Article
• Language: English
• Subjects: Animals; CD5 Antigens - genetics; CD5 Antigens - immunology; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; Cell Survival - immunology; Cells, Cultured; Cytokines - immunology; Gene Expression Regulation; homeostasis; Homeostasis - drug effects; Homeostasis - immunology; IL‐7; Immunologic Factors - metabolism; Immunologic Factors - pharmacology; Interleukin-7 - metabolism; Interleukin-7 - pharmacology; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; naïve T cells; Outstanding Observation; Receptors, Interleukin-7 - genetics; Receptors, Interleukin-7 - immunology; Signal Transduction - drug effects; Signal Transduction - immunology; signaling
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2011.5

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 We show here that even when withdrawn from self‐peptide‐induced TCR stimulation, CD8+ T cells exhibit heterogeneous responses to interleukin‐7 (IL‐7) that are mechanistically associated with IL‐7R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 CD5hi and CD5lo T cells survive equivalently in the presence of saturating IL‐7 levels in vitro, CD5hi T cells proliferate more robustly. Conversely, CD5lo T cells exhibit prolonged survival when withdrawn from homeostatic stimuli.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 CD5hi 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 CD5lo and CD5hi 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 CD5hi 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 CD5hi IL‐7Rhi nor CD5lo IL‐7Rlo 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.