Abstract
CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.
Highlights
CD4+ T cells are essential in the setting of chronic viral infections, as demonstrated most clearly in human immunodeficiency virus (HIV) infection, where the progressive depletion of CD4+ helper T cells is accompanied by a progressive dysfunction of CD8+ T cells, which adopt an exhausted phenotype characterized by the expression of multiple inhibitory receptor such as PD-1, TIGIT, and LAG-3, the loss of proliferative and cytokine secretion capacity, and the loss of cytotoxic activity [28,29]
T follicular helper (Tfh) cells are characterized by a high expression of PD-1, of the CXCR5 chemokine receptor, which drives homing to germinal centers, and of the IL-21 cytokine, which provides survival signals to B cells [77]
It has long been recognized that amplification of high-affinity T cell receptor (TCR) clonotypes in antiviral CD8+ T cells is associated with the control of chronic viral infections, as shown for instance in animal models of infection by vaccinia virus, herpes simplex virus-1, equine infectious anemia virus, paramyxovirus simian virus-5, and respiratory syncytial virus (RSV) [124,125,126]
Summary
The licensing process involves upregulation of CD40 ligand (CD40L) at the surface of CD4+ T cells recognizing their cognate antigen presented by DCs, followed by CD40-CD40L interactions that induce the upregulation of MHC-I and costimulatory molecules CD80/CD86 and CD70 at the DC surface. In the setting of acute viral infections, the induction of an efficient CD8+ T cell response does not always require CD4+ T cell help Some viruses, such as vesicular stomatitis virus (VSV) and influenza virus, induce sufficient DC maturation to prime antiviral CD8+ T cell in the absence of help [22].
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