Search

Systems immunology lacks a framework with which to derive theoretical understanding from high-dimensional datasets. We combined a robotic platform with machine learning to experimentally measure and theoretically model CD8 + T cell activation. High-dimensional cytokine dynamics could be compressed onto a low-dimensional latent space in an antigen-specific manner (so-called "antigen encoding"). We used antigen encoding to model and reconstruct patterns of T cell immune activation. The model delineated six classes of antigens eliciting distinct T cell responses. We generalized antigen encoding to multiple immune settings, including drug perturbations and activation of chimeric antigen receptor T cells. Such universal antigen encoding for T cell activation may enable further modeling of immune responses and their rational manipulation to optimize immunotherapies.

T lymphocytes’ ability to discriminate between structurally related antigens has been attributed to the unique signaling properties of the T cell receptor. However, recent studies have suggested that the output of this discrimination process is conditioned by environmental cues. Here, we demonstrate how the IL-2 cytokine, collectively generated by strongly activated T cell clones, can induce weaker T cell clones to proliferate. We identify the PI3K pathway as being critical for integrating the antigen and cytokine responses and for controlling cell-cycle entry. We build a hybrid stochastic/deterministic computational model that accounts for such signal synergism and demonstrates quantitatively how T cells tune their cell-cycle entry according to environmental cytokine cues. Our findings indicate that antigen discrimination by T cells is not solely an intrinsic cellular property but rather a product of integration of multiple cues, including local cues such as antigen quality and quantity, to global ones like the extracellular concentration of inflammatory cytokines.

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.

T cells discriminate between peptide-MHC complexes on the surfaces of antigen presenting cells to enact appropriate downstream responses. Great progress has been made over the last 15 years in understanding varied aspects of T cell activation on short timescales (minutes), yet the mechanics and significance of long term T cell receptor signaling (hours or days) remain unclear. Furthermore, there remain some controversies regarding the correlation of the biophysical parameters of ligand-receptor interactions with the scaling of downstream effector functions. Here we review recent studies that emphasize the importance of long-term engagement of antigens to fine-tuning the activation of T cells over the duration of the complete immune response. We discuss how T cells dynamically regulate T cell receptor signaling via antigen crosstalk, competition and consumption to accurately counter antigenic challenges., (Copyright © 2012 Elsevier Ltd. All rights reserved.)