Overcoming CD4 T helper cell fate restrictions to enhance CD8 T cell and B cell immunity to control persistent LCMV infection

Abstract

Abstract Persistent viral infection inhibits CD4 Th1 responses, resulting in loss of the CD8 T cell helping Th1 subset and accumulation of B cell helping Tfh cells. Yet, the mechanisms that inhibit CD4 Th1 differentiation and the repercussions of loss of Th1 cells on viral control are unclear. Herein, we demonstrate that the dual upregulation of PD-L1 and IL-10 by chronic type I interferon (IFN-I) signaling during persistent infection suppresses CD4 Th1 priming. Therapeutic blockade of IL-10R and PD-L1 could restore the differentiation of new CD4 Th1 cells, highlighting a new function for PD-L1 to co-inhibit CD4 Th1 priming and identifying a new combinatorial suppressive mechanism during persistent infection. However, CD4 Th1 cells generated by blocking IFN-I signaling in vivo could not be sustained, giving way to a Tfh based response and predominant help to B cells. In vitro polarized virus-specific CD4 Th1 cells also converted towards Tfh cells, however maintained a population of Th1 cells that could enhance exhausted CD8 T cell responses and promote augmented viral clearance. Interestingly, virus-specific CD4 Th17 and Treg cells were also redirected towards Tfh as persistent infection progressed. Thus, our studies have important implications for stability of de novo activated and immunotherapeutic T cells and demonstrate that the redirection away from Th1 responses is a mechanism of immunosuppression to limit the control of persistent viral infection.