Abstract
Continuous contact with self-major histocompatibility complex ligands is essential for the survival of naive CD4 T cells. We have previously shown that the resulting tonic TCR signaling also influences their fate upon activation by increasing their ability to differentiate into induced/peripheral regulatory T cells. To decipher the molecular mechanisms governing this process, we here focus on the TCR signaling cascade and demonstrate that a rise in intracellular calcium levels is sufficient to modulate the phenotype of mouse naive CD4 T cells and to increase their sensitivity to regulatory T-cell polarization signals, both processes relying on calcineurin activation. Accordingly, in vivo calcineurin inhibition leads the most self-reactive naive CD4 T cells to adopt the phenotype of their less self-reactive cell-counterparts. Collectively, our findings demonstrate that calcium-mediated activation of the calcineurin pathway acts as a rheostat to shape both the phenotype and effector potential of naive CD4 T cells in the steady-state.
Highlights
T-cell precursors originate in the bone-marrow and are educated in the thymus through processes called positive and negative selections, which result in MHC-restriction and self-tolerance, respectively (Stritesky et al, 2012)
We have recently shown that CD4 TN cells with the highest avidity for self-MHC (Ly-6C- CD4 TN cells) have a biased commitment toward the iTreg/pTreg-cell lineage (Martin et al, 2013)
In the steady-state, naive T cells continually recirculate between the blood, lymph and secondary lymphoid organs, scanning dendritic cells (DCs) for the presence of foreign antigens
Summary
T-cell precursors originate in the bone-marrow and are educated in the thymus through processes called positive and negative selections, which result in MHC-restriction and self-tolerance, respectively (Stritesky et al, 2012). As a naive T cell travels around the body, it repeatedly interacts with antigen-presenting cells that display Self-antigens, which triggers a low level of signaling in the T cell While this background signaling was known to help the T cell survive, in 2013, researchers reported that: it makes the T cell more responsive to foreign antigens; and it shapes how these cells will respond when activated. Experimental evidences indicate that self-MHC recognition in the periphery is required to maintain T cells in a state of responsiveness toward foreign antigen (Persaud et al, 2014; Stefanovaet al., 2002; Wulfing et al, 2002), suggesting a crucial role for self-MHC mediated ‘education’ and TCR selfreactivity in determining the intrinsic functional attributes of CD4 TN cells This steadystate tonic TCR signaling was shown to influence CD4 TN-cell effector fate by increasing the magnitude of their response toward their cognate antigens. By using transcriptomic and phenotypic approaches as well as in vitro and in vivo assays, we have identified the Ca2+ signaling pathway as key for the acquisition of both the phenotype of the most selfreactive CD4 TN cells and their enhanced cell-intrinsic ability to commit into regulatory T cells upon activation in vitro (iTreg) and in vivo (pTreg)
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