Correlates of Follicular Helper Bias in the CD4 T Cell Response to a Retroviral Antigen

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.

Friend retrovirus studies reveal complex interactions between intrinsic, innate and adaptive immunity

“…In contrast to the typically balanced Th1-Tfh response in other viral infections, the CD4+ T cell response to FV infection was recently shown to be heavily skewed towards Tfh differentiation (Danelli, Donnarumma and Kassiotis 2018). Biased Tfh differentiation in response to FV infection was clearly promoted by TCR signal strength, as measured by a reporter for TCR signaling and experimentally manipulated with altered epitopes, but was not affected by TCR clonotypic avidity (Danelli, Donnarumma and Kassiotis 2018). Notably, the difference in TCR signal strength experienced by Th1 and Tfh A b /env 124-138 -reactive CD4+ T cells, was not due to differences in the avidities of their respective TCR repertoires, but rather a consequence of their differentiation and interaction with distinct subsets of APC (Danelli, Donnarumma and Kassiotis 2018).…”

“…In contrast to the typically balanced Th1-Tfh response in other viral infections, the CD4+ T cell response to FV infection was recently shown to be heavily skewed towards Tfh differentiation (Danelli, Donnarumma and Kassiotis 2018). Biased Tfh differentiation in response to FV infection was clearly promoted by TCR signal strength, as measured by a reporter for TCR signaling and experimentally manipulated with altered epitopes, but was not affected by TCR clonotypic avidity (Danelli, Donnarumma and Kassiotis 2018).…”

“…Biased Tfh differentiation in response to FV infection was clearly promoted by TCR signal strength, as measured by a reporter for TCR signaling and experimentally manipulated with altered epitopes, but was not affected by TCR clonotypic avidity (Danelli, Donnarumma and Kassiotis 2018). Notably, the difference in TCR signal strength experienced by Th1 and Tfh A b /env 124-138 -reactive CD4+ T cells, was not due to differences in the avidities of their respective TCR repertoires, but rather a consequence of their differentiation and interaction with distinct subsets of APC (Danelli, Donnarumma and Kassiotis 2018). This central role for APCs also underlies the induction of distinct ratios of Th1, Tfh or cytotoxic CD4+ T cells by different vaccine vectors or immunization regimens in the FV model (Donnarumma et al 2016;Shen et al 2018).…”

“…Moreover, they can also mediate direct anti-FV functions (Hasenkrug, Brooks and Dittmer 1998;Iwashiro et al 2001b;Nair et al 2010). Although less studied than their CD8+ counterparts, several CD4+ T cell subsets are induced in response to FV infection (Iwashiro et al 1993;Antunes et al 2008;Pike et al 2009;Nair et al 2010;Danelli, Donnarumma and Kassiotis 2018). Mouse CD4+ T cells of the H2-A b haplotype target numerous epitopes encoded by F-MLV gag, pol and env (Messer, Lavender and Hasenkrug 2014).…”

“…Early studies highlighted an important role for CD4+ T cells in providing help for the antibody response (Super et al 1998;Hasenkrug 1999). Indeed, F-MuLV-reactive CD4+ T cells demonstrate robust follicular helper (Tfh) differentiation, which can be much stronger than that of CD4+ T cells responding to other viral infections (Ploquin, Eksmond and Kassiotis 2011;Danelli, Donnarumma and Kassiotis 2018). F-MuLV-reactive CD4+ T cells also promote cellular immunity.…”