Abstract
CD4+ T cell differentiation is influenced by a plethora of intrinsic and extrinsic factors, providing the immune system with the ability to tailor its response according to specific stimuli. Indeed, different classes of pathogens may induce a distinct balance of CD4+ T cell differentiation programmes. Here, we report an uncommonly strong bias toward follicular helper (Tfh) differentiation of CD4+ T cells reactive with a retroviral envelope glycoprotein model antigen, presented in its natural context during retroviral infection. Conversely, the response to the same antigen, presented in different immunization regimens, elicited a response typically balanced between Tfh and T helper 1 cells. Comprehensive quantitation of variables known to influence Tfh differentiation revealed the closest correlation with the strength of T cell receptor (TCR) signaling, leading to PD-1 expression, but not with surface TCR downregulation, irrespective of TCR clonotypic avidity. In contrast, strong TCR signaling leading to TCR downregulation and induction of LAG3 expression in high TCR avidity clonotypes restrained CD4+ T cell commitment and further differentiation. Finally, stunted Th1 differentiation, correlating with limited IL-2 availability in retroviral infection, provided permissive conditions for Tfh development, suggesting that Tfh differentiation is the default program of envelope-reactive CD4+ T cells.
Highlights
Several divergent and often competing programmes of CD4+ T cell differentiation are well recognized, leading to the development of distinct functional subsets, including T helper (Th) 1, 2, or 17 cells, follicular helper (Tfh) cells, and regulatory T (Treg) cells [1,2,3,4,5]
PD-1 and LAG3 blockade during Friend virus (FV) infection drove efficient differentiation of uncommitted Th0 env-reactive EF4.1 CD4+ T cells into toward follicular helper (Tfh) cells, which again formed the large majority, with a small numerical increase in Th1 cells and a small numerical loss of Th0 cells (Figure 3G). These results suggested that FV infection induces primarily Tfh differentiation of env-reactive EF4.1 CD4+ T cells, partly restrained by inhibitory receptor expression, in turn induced by strong T cell receptor (TCR) signaling
It is well recognized that both T cell-intrinsic and T cellextrinsic factors shape the balance of CD4+ T cell differentiation into distinguishable functional subsets [1,2,3,4,5,6,7,8]
Summary
Several divergent and often competing programmes of CD4+ T cell differentiation are well recognized, leading to the development of distinct functional subsets, including T helper (Th) 1, 2, or 17 cells, follicular helper (Tfh) cells, and regulatory T (Treg) cells [1,2,3,4,5]. The relative balance of CD4+ T cell differentiation to one or more of these functional subsets largely depends on a multitude of T cell-extrinsic factors, with the cytokine milieu naïve T cells encounter during the priming phase playing a major role [1,2,3,4,5]. CD4+ T cell differentiation can be shaped by T cell-intrinsic properties, such as the relative affinity of the T cell receptor (TCR), favoring development of particu lar subsets [6,7,8]. Acute viral infections typically induce a CD4+ T cell response that is almost exclusively composed of Tfh and Th1 cells, in approximately equal proportion. The ratio of Tfh to Th1 cells in the CD4+ T cell response to acute lymphocytic choriomeningitis virus (LCMV) has been amply reported
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