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Immunol Cell Biol. 2011 Jul;89(5):581-94. doi: 10.1038/icb.2011.5. Epub 2011 Feb 22.

Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of naïve CD8(+) T cells.

Palmer MJ, Mahajan VS, Chen J, Irvine DJ, Lauffenburger DA.

Source

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract

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 We show here that even when withdrawn from self-peptide-induced TCR stimulation, CD8(+) T cells exhibit heterogeneous responses to interleukin-7 (IL-7) that are mechanistically associated with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 Conversely, CD5(lo) T cells exhibit prolonged survival when withdrawn from homeostatic stimuli.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.

PMID:: 21339767; [PubMed - indexed for MEDLINE]
PMCID:: PMC3342499

Free PMC Article

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Figure 1

CD5 expression levels stratify a hierarchy in the IL-7-induced proliferation capacities of CD8⁺ T cells. (a) CD5 surface expression of freshly isolated OT-1 and F5 TCR-tg naïve (CD44^lo) CD8⁺ T cells (top panel) and their proliferation when cultured in vitro at low density (∼2 × 10⁵ cells per ml) with 0.1 or 10 ng ml⁻¹ of IL-7, as assayed by CFSE dilution after 7 days (middle panels), and quantified as the fraction of cells divided (bottom panel). (b) Proliferation of OT-1 and F5 TCR-tg naïve (CD44^lo) CD8⁺ T cells when cultured in vitro at low density with 0.1 or 10 ng ml⁻¹ of IL-7 as measured by the fraction of cells expressing the nuclear proliferation antigen Ki67 for cells either freshly isolated (top panels) or rested overnight (16 h) in cytokine-free media before stimulation (bottom panels). ^*P<0.05 between 0.1 and 10 ng ml⁻¹ conditions and between fresh and rested cells. (c) As described in a, except for OT-1 and F5 TCR-tg CD8⁺ memory-like cells generated in vitro through activation of naïve (CD44^lo) OT-1 and F5 TCR-tg CD8⁺ T cells with plate-coated anti-CD3 and 20 ng ml⁻¹ IL-2 for 3 days, followed by incubation with 40 ng ml⁻¹ IL-15 for 3 days and overnight rest in cytokine-free media before IL-7 stimulation. (d) Decay of CD5 surface expression of freshly isolated OT-1 and F5 TCR-tg naïve (CD44^lo) CD8⁺ T cells cultured with 0, 0.1, 1 or 10 ng ml⁻¹ IL-7, normalized to initial expression for each cell type (top panel), or to initial CD5 expression on OT-1 cells (bottom panel). (e) As described in a, except for freshly isolated C57BL/6 naïve (CD44^lo) CD8⁺ T cells, sorted into CD5^hi and CD5^lo expressing fractions. (f) As described in a, except for freshly isolated naïve H-2K^b−/−D^b−/− (CD44^lo) CD8⁺ T cells from C57BL/6.Rag1^−/− mice transplanted with C57BL/6.H-2K^b−/−D^b−/− bone marrow, sorted into CD5^hi and CD5^lo expressing fractions. Data (a–f) are representative of two independent experiments (error bar=±1s.d.).

Signaling thresholds govern heterogeneity in IL-7-receptor-mediated responses of na?ve CD8+ T cells

Immunol Cell Biol. 2011 July;89(5):581-594.