Synergistic CD40 signaling on APCs and CD8 T cells drives efficient CD8 response and memory differentiation

Abstract

The role of CD4 help during CD8 response and memory differentiation has been clearly demonstrated in different experimental models. However, the exact mechanisms of CD4 help remain largely unknown and preclude replacement therapy to develop. Interestingly, studies have shown that administration of an agonist aCD40ab can substitute CD4 help in vitro and in vivo, whereas the targets of this antibody remain elusive. In this study, we address the exact role of CD40 expression on APCs and CD8 T cells using aCD40ab treatment in mice. We demonstrate that aCD40 antibodies have synergetic effects on APCs and CD8 T cells. Full efficiency of aCD40 treatment requires CD40 expression on both populations: if one of these cell populations is CD40-deficient, the CD8 T cell response is impaired. Most importantly, direct CD40 signaling on APCs and CD8 T cells affects CD8 T cell differentiation differently. In our model, CD40 expression on APCs plays an important but dispensable role on CD8 T cell expansion and effector functions during the early phase of the immune response. Conversely, CD40 on CD8 T cells is crucial and nonredundant for their progressive differentiation into memory cells. Altogether, these results highlight that CD40-CD40L-dependent and independent effects of CD4 help to drive a complete CD8 T cell differentiation.

Novel Cell-Penetrating Peptide-Based Vaccine Induces Robust CD4+ and CD8+ T Cell–Mediated Antitumor Immunity

“…2B), although this may be a consequence of the rat origin of this antibody. Despite the overall reduction in multimer þ cells, it is possible that anti-CD40 antibody induces more central or effector memory T-cell populations (32). Consistent with this hypothesis, we observed elevated proportions of a central memory-like population within the multimer…”

Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B

“…Another nonmutually exclusive hypothesis is that activated platelets may favor CD8 + T-cell division. Along these lines, we have proposed that the activation-dependent expression of platelet CD40 ligand contributes to the expansion phase of virus-specific CD8 + T cells, resulting in their accumulation at sites of infection (24); this effect may reflect direct interaction of activated platelets with CD8 + T cells that express CD40 (25,26). Others have indicated that platelet CD40 ligand has the potential to enhance virus-specific CD8 + T-cell responses indirectly, mostly by promoting the maturation of dendritic cells (27,28).…”

CD40 Is Required for Protective Immunity against Liver Stage Plasmodium Infection

“…However, using a model in which female CD8+ T cells respond to male HY antigen – a system which presumably does not carry as many danger signals as bacterial or viral infection – CD40 was required on both the APC and the CD8+ T cell to generate effective memory responses. Specifically, CD40 expressed on the APC was necessary for clonal expansion while CD40 on the CD8+ T cell itself was required for memory CD8+ T cell formation (26, 27). Whether CD40 plays any role in liver-stage Plasmodium infection has never been examined and thus we were interested in whether the requirement for CD40 mirrored that of bacterial and viral models or that of non-inflammatory antigens.…”

“…While WT CD8+ T cells in WT hosts downregulated Pdcd1 , Lag3 , and Havcr1 (which encode the inhibitory receptors PD1, LAG3, and TIM3), WT CD8+ T cells in CD40−/− hosts didn’t downregulate these genes as much, and CD40−/− CD8+ T cells appear to have upregulated Havcr2 and Lag3. CD40−/− CD8+ T cells have been observed to become unresponsive to stimuli over time, characteristic of exhausted cells (27). In line with our results, CD40 expressed on CD8+ T cells has been implicated in the rescue of exhausted T cells in chronic Hepatitis B virus and Toxoplasma gondii infections (24, 78).…”

“…In non-inflammatory model systems, CD40 expressed on the CD8+ T cell is critical for the development of an effective memory response, whereas in viral and bacterial infections it is not required, and CD40 on the APC drives the CD8+ T cell response (25–27). Whether immunity to an intracellular eukaryotic parasite such as the liver stage of Plasmodium relies on CD40 as a route of CD4+ T cell help is unclear.…”