The sensitivity of T cells to interleukin-2 (IL-2) can vary by three orders of magnitude and is determined by the surface densities of the IL-2 receptor α subunits.Regulatory T cells inflict a double hit on effector T cells by lowering the bulk IL-2 concentration as well as the sensitivity of effector T cells to this crucial cytokine.This double hit deprives weakly activated effector T cells of pSTAT5 survival signals while having only minimal effects on strongly activated effector cells that express increased levels of the IL-2 receptor.Short-term signaling differences lead to a differential functional in terms of proliferation and cell division: regulatory T cell specifically suppress weakly activated effector T cells even at large numbers; small numbers of strongly activated effector T cells overcome the suppression.

The strength of T-cell receptor (TCR) stimulation and subsequent T-cell response depend on a combination of peptide-major histocompatibility complex (pMHC) density and potency. By comparing two different pMHC at doses yielding similar proliferation in vivo, we have highlighted unexpected differences in the qualitative and quantitative effects of TCR ligand. Measurements of cytokine sensitivity and two-photon imaging of T cell-dendritic cell (T-DC) interactions reveal discrimination between comparably weak stimuli resulting from either decreased pMHC potency or pMHC density. In addition, TCR-induced genes in broad gene expression profiles segregate into two groups: one that responds to cumulative TCR signal and another that responds to pMHC quality, independent of quantity. These observations suggest that models of TCR ligand discrimination must account for disparate sensitivity of downstream responses to specific influences of pMHC potency.T cells recognize peptide antigen in the context of MHC. During this process, the quality and quantity of the ligands determine the cumulative level of downstream signaling. Evidence suggests that T-cell receptor (TCR) can detect pMHC with remarkable sensitivity, responding to fewer than 10 pMHC complexes (1, 2), and several models of TCR triggering have been proposed to explain the ability of TCR to recognize various pMHC ligands with such sensitivity, above the noise of abundant self-pMHC (3). Both TCR/pMHC affinity and off-rate can correlate with the potency of stimulation, depending on the on-rate of the ligand (4, 5). Thus, the diverse nature of TCR/pMHC binding properties may limit the applicability of characterizing ligand quality on the basis of any single biochemical or thermodynamic parameter. Here we use the term potency to more generally reflect qualitative differences in TCR/pMHC binding parameters.It is known from in vitro studies that the strength of TCR/ pMHC interactions sets dose requirements for initiation of a variety of T-cell responses (6). Higher peptide concentrations can often compensate for weaker TCR/pMHC interactions to yield equivalent maximal responses in vitro. Thus, in studying the effects of altering the individual components of cumulative TCR signal (i.e., the potency or density of antigen), it is difficult to discriminate between distinct influences of TCR/pMHC binding parameters and the impact of shifting the overall TCR signal. For example, whereas recent in vivo studies have demonstrated that altered TCR ligands can induce large differences in the degree of proliferation, cytokine production and memory formation (7,8), it is unclear whether the observed functional consequences are specific to qualitative differences in these ligands or could be similarly influenced by the amount of antigen. Only by manipulating both variables within the same system is it possible to determine whether T cells can discern specific influences of pMHC quality and quantity. Thus, we compared weak stimuli in vivo, resulting from either decreased pMHC potency (la...

Variability within isogenic T cell populations yields heterogeneous ‘local’ signaling responses to shared antigenic stimuli, but responding clones may communicate ‘global’ antigen load through paracrine messengers, such as cytokines. Such coordination of individual cell responses within multicellular populations is critical for accurate collective reactions to shared environmental cues. However, cytokine production may saturate as a function of antigen input, or be dominated by the precursor frequency of antigen-specific T cells. Surprisingly, we found that T cells scale their collective output of IL-2 to total antigen input over a large dynamic range, independently of population size. Through experimental quantitation and computational modeling, we demonstrate that this scaling is enforced by an inhibitory cross-talk between antigen and IL-2 signaling, and a nonlinear acceleration of IL-2 secretion per cell. Our study reveals how time-integration of these regulatory loops within individual cell signaling generates scaled collective responses and can be leveraged for immune monitoring.DOI: http://dx.doi.org/10.7554/eLife.01944.001