Recall Responses by Helpless Memory CD8+ T Cells Are Restricted by the Up-Regulation of PD-1

Abstract

CD4 help is crucial for memory CD8+ T cell development, yet the mechanisms of CD4 help and why (CD4) helpless memory CD8+ T cells elicit poor recall responses are currently not well understood. In this study we investigated these questions using an in vivo acute virus infection model. We show herein that CD4 help during priming is required for memory CD8+ T cell differentiation, and that stimulation of CD40 during priming rescues the helpless defects in the absence of CD4+ T cells. The defective recall response by helpless memory cells did not correlate with the amount of cell death and was independent of TRAIL. However, helpless memory cells excessively up-regulated the inhibitory receptor PD-1 (programmed cell death-1), and PD-1 blockade enhanced the recall response of helpless memory cells. Furthermore, providing IL-2 signaling in vivo during the recall response reduced PD-1 expression and rescued the recall response of helpless memory cells. Our study identifies molecular pathways involved in CD4 help for memory CD8+ T cell generation that are independent of TRAIL, and it provides therapeutic implications that helpless memory cell function can be restored at multiple stages through various immunological interventions.

CD4 + T cell regulation of CD25 expression controls development of short-lived effector CD8 + T cells in primary and secondary responses

“…For instance, no defect has been observed for memory CD8 + T cells developing in the absence of CD40 signaling during LM infection (33). In contrast, CD40 signaling appears to be critical for full differentiation of memory CD8 + T cells following influenza A virus, murine γ-herpesvirus, and intranasal vaccinia virus infections (23,29). Our results showed that the CD8 + T cell response to i.p.…”

“…However, even when CD4 + T cell help is apparently not required for primary expansion, the "helpless" memory CD8 + T cells respond poorly to challenge (17)(18)(19), but there is disagreement in the literature on this point (21,22). Additionally, in the absence of CD4 + T cell help, immune responses to intranasal infection with vaccinia virus-Western Reserve (VV-WR) or murine γ-herpesvirus generate normal primary responses, but secondary recall is inhibited through the up-regulation of PD-1 (23). Although the critical signal provided by CD4 + T cell help appears to be the ligation of CD40 on antigen presenting cells, IL-2 production by CD4 + T cells may also play a role (24)(25)(26).…”

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

“…On pDCs, CD40 ligation has been described to augment the production of IL-6, thereby facilitating generation of antibody producing plasma cells (Jego et al, 2003). Furthermore, CD40 signaling can aid effective activation of T cells or prevent T cell exhaustion (Krug et al, 2001;Fonteneau et al, 2003;Tel et al, 2013;Fuse et al, 2009;Isogawa et al, 2013). In CHB patients low and exhausted T cells are consistently observed and held responsible for the inability to clear HBV (Ferrari et al, 1990;Jung et al, 1991;Boni et al, 2007Boni et al, , 2012Bertoletti and Ferrari, 2016).…”

Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection

“…One model that has recently attracted much attention stems from the discovery that the inhibitory programmed death-1 (PD-1), a cell-surface molecule that marks exhausted T cells, is generally upregulated on pathogen-specific CD8 + T cells in chronic viral diseases, including HCV (4,5). Because the PD-1/programmed death ligand 1 (PD-L1) axis operates primarily under conditions of sustained high levels of Ag stimulation and inadequate help (6) to turn off Ag-specific CD8 to prevent immune-mediated damage, chronic pathogens end up taking advantage of this inhibitory pathway to establish persistence in the host. This negative regulator has become a therapeutic target of choice because Ab blocking of PD-L1 reinvigorates exhausted CD8 cells to control chronic SIV infection in macaques (7).…”