T cells translate individual, quantal activation into collective, analog cytokine responses via time-integrated feedbacks

Abstract

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

The Case for Absolute Ligand Discrimination: Modeling Information Processing and Decision by Immune T Cells

“…Biochemically, this implied that the IL-2 output of a population of T cells would have a ceiling of 10 pM, as the concentration of cytokine required to induce IL-2 signaling and subsequent shutdown to IL-2 secretion [66]. However, detailed quantitation of the biochemistry of the system unraveled a negative cross-talk from the antigen signaling response to the IL-2 response pathway [60]. When measuring the phosphorylation of the ST AT 5 transcription factor downstream of IL-2 sensing, Tkach et al uncovered a surprising convolution between response to pM HC antigens and I L-2 cytokine: Such initial attempt by Tkach et al [60] was based on detailed biochemical modeling with explicit biochemistry being implemented.…”

“…However, detailed quantitation of the biochemistry of the system unraveled a negative cross-talk from the antigen signaling response to the IL-2 response pathway [60]. When measuring the phosphorylation of the ST AT 5 transcription factor downstream of IL-2 sensing, Tkach et al uncovered a surprising convolution between response to pM HC antigens and I L-2 cytokine: Such initial attempt by Tkach et al [60] was based on detailed biochemical modeling with explicit biochemistry being implemented. Additional experiments revealed additional functional relevance for the secretion of IL-2, as a global regulator of self/not-self discrimination: Voisinne et al probed the proliferation response of a population of T cells containing multiple clones of diverse specificity (i.e.…”

“…Deriving an intensive output (i.e. an output that is independent from the size of the system) for a population of T cells has been observed in very related [19,29,60,67]. In particular, T cells can rely on such cell-to-cell communications to achieve higher levels of immune recognition.…”

“…This study demonstrated that strongly activated T cell clones could induce the activation and proliferation of neighboring weakly activated T cell clones [65]: this previously-undocumented phenomenon of propagating T cell activation was termed "T cell co-optation". Similarly to previous studies [2,19,60], an experimentally-derived biochemically-explicit model of such multi scale integration was introduced to account for such lymphocyte co-optation. Overall, it was demonstrated that the addition of antigen signals (read locally through the TCR pathway) and cytokine signals (read globally through the IL-2 pathway) decides T cell fate.…”

“…through secretion and consumption of cytokines. In particular, Tkach et al measured experimentally how much cytokine accumulates in the supernatant of T cells that were activated in vitro [60] (Fig. 5).…”