Abstract
The adaptive immune response is initiated by the interaction of the T cell antigen receptor/CD3 complex (TCR) with a cognate peptide bound to a MHC molecule. This interaction, along with the activity of co-stimulatory molecules and cytokines in the microenvironment, enables cells to proliferate and produce soluble factors that stimulate other branches of the immune response for inactivation of infectious agents. The intracellular activation signals are reinforced, amplified and diversified by a complex network of biochemical interactions, and includes the activity of molecules that modulate the activation process and stimulate the metabolic changes necessary for fulfilling the cell energy demands. We present an approach to the analysis of the main early signaling events of T cell activation by proposing a concise 46-node hybrid Boolean model of the main steps of TCR and CD28 downstream signaling, encompassing the activity of the anergy factor Ndrg1, modulation of activation by CTLA-4, and the activity of the nutrient sensor AMPK as intrinsic players of the activation process. The model generates stable states that reflect the overcoming of activation signals and induction of anergy by the expression of Ndrg1 in the absence of co-stimulation. The model also includes the induction of CTLA-4 upon activation and its competition with CD28 for binding to the co-stimulatory CD80/86 molecules, leading to stable states that reflect the activation arrest. Furthermore, the model integrates the activity of AMPK to the general pathways driving differentiation to functional cell subsets (Th1, Th2, Th17, and Treg). Thus, the network topology incorporates basic mechanism associated to activation, regulation and induction of effector cell phenotypes. The model puts forth a conceptual framework for the integration of functionally relevant processes in the analysis of the T CD4 cell function.
Highlights
Antigen-driven T cell responses are performed by the combined activity of many intracellular reactions acting in concerted cascades to reinforce, amplify, diversify and regulate the initial antigenic signal
It incorporates signaling events induced by the T cell antigen receptor/CD3 complex (TCR) and the co-stimulation elicited by the interaction of CD80/86 with CD28, the downstream expression of cytotoxic T lymphocyte antigen-4 (CTLA-4) with displacement of CD28 from the CD80/86 ligand, the activity of the nutrient sensor AMPK, and the effect of cytokines able to induce differentiation to effector phenotypes
The mathematical model predicts stable states consistent with functional features of T CD4 lymphocytes: activation under TCR and CD28 stimulation, anergy in the absence of one of these cues, shutdown of the activation cascades by CTLA4, and differentiation to effector cell phenotypes coupled to corresponding metabolic switches
Summary
Antigen-driven T cell responses are performed by the combined activity of many intracellular reactions acting in concerted cascades to reinforce, amplify, diversify and regulate the initial antigenic signal. These processes lead to the clonal expansion and differentiation of the T cells into a variety of effector phenotypes. The activation process includes signaling for its own regulation and induction of the metabolic changes necessary to meet cellular energy demands. Signaling from the TCR and CD28 converge in the activation of the AP-1, NFAT, and NF-κB transcription factors, which are necessary for the expression of IL-2, a cytokine essential for cell survival and proliferation. Upon efficient activation, signals that regulate the whole processes are elicited, being those mediated by CTLA4 the most well-studied
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