Abstract
Persistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) “exhaustion”, i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1+PD-1+ CD8+ T cells as precursors of the terminally exhausted CTL pool. These “predysfunctional” CTLs are suggested to respond to PD-1 targeted therapy by giving rise to a pool of functional CTLs. Supported by gene expression analyses, we present a model in which lack of CD4+ T cell help during CD8+ T cell priming results in the formation of predysfunctional CTLs. Our model implies that predysfunctional CTLs are formed during priming and that the remedy for CTL dysfunction is to provide “help” signals for generation of optimal CTL effectors. We substantiate that this may be achieved by engaging CD4+ T cells in new CD8+ T cell priming, or by combined PD-1 blocking and CD27 agonism with available immunotherapeutic antibodies.
Highlights
In chronic infection and cancer, CD8+ T cells upregulate coinhibitory receptors and display impaired proliferative and cytotoxic capacities, a phenomenon described as “T cell exhaustion”
We present a novel model posing that virus-specific or tumorspecific, predysfunctional TCF-1+ CD8+ T cells in chronic infection or cancer result from priming in the absence of CD4+ T cell help
We have shown in the mouse vaccination model, that the effects of CD4+ T cell help on the cytotoxic T lymphocyte (CTL) response could be mimicked by combined PD-1-blockade and CD27 agonism [99]
Summary
In chronic infection and cancer, CD8+ T cells upregulate coinhibitory receptors and display impaired proliferative and cytotoxic capacities, a phenomenon described as “T cell exhaustion”. We first discuss the recent literature on CD8+ T cell predysfunction and exhaustion in a key mouse model of chronic virus infection. By connecting studies on infection and cancer, we integrate supporting arguments for this concept We synthesize these recent insights into a model of progressive fate commitment of primed CD8+ T cells. Supported by gene expression analyses, we introduce the novel perspective that the predysfunctional differentiation state results from CD8+ T cell priming in the absence of CD4+ T cell help. This viewpoint implies that reinvigoration of predysfunctional CD8+ T cells may be achieved by addition of “help” signals.
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