Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection

Abstract

CD4 T cells play a critical role in regulating CD8 T-cell responses during chronic viral infection. Several studies in animal models and humans have shown that the absence of CD4 T-cell help results in severe dysfunction of virus-specific CD8 T cells. However, whether function can be restored in already exhausted CD8 T cells by providing CD4 T-cell help at a later time remains unexplored. In this study, we used a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Adoptive transfer of LCMV-specific CD4 T cells into chronically infected mice restored proliferation and cytokine production by exhausted virusspecific CD8 T cells and reduced viral burden. Although the transferred CD4 T cells were able to enhance function in exhausted CD8 T cells, these CD4 T cells expressed high levels of the programmed cell death (PD)-1 inhibitory receptor. Blockade of the PD-1 pathway increased the ability of transferred LCMV-specific CD4 T cells to produce effector cytokines, improved rescue of exhausted CD8 T cells, and resulted in a striking reduction in viral load. These results suggest that CD4 T-cell immunotherapy alone or in conjunction with blockade of inhibitory receptors may be a promising approach for treating CD8 T-cell dysfunction in chronic infections and cancer.

Positive selection of mC46-expressing CD4+ T cells and maintenance of virus specific immunity in a primate AIDS model

“…34 In addition to CD4 1 T cells playing a central role in the initial acute phase of viral infection, they are also critical for maintaining functionality and diversity of CTL responses during chronic stages of disease. 35 The results obtained in this study demonstrate that both SHIV-specific CD8 36 The reversal of CD8 1 T-cell exhaustion was…”

Broadening CD4+and CD8+T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes

“…Adding to this, a strong initial response against dominant epitopes tends to wane over time, as continued antigen stimulation may drive polyfunctional T cells toward an exhausted, dysfunctional state (65,66). Recently, it has been speculated that an ideal vaccine against viruses resulting in chronic infections should not only generate robust cellular responses against strongly recognized epitopes, but should also aim to induce responses against subdominant epitopes, which may offset potential T cell exhaustion by inducing new multifunctional responses against viral epitopes that are not heavily targeted during infection (67).…”

Helping Themselves: Optimal Virus-Specific CD4 T Cell Responses Require Help via CD4 T Cell Licensing of Dendritic Cells

“…For example, it may be useful to engineer inactivated viruses or subunit vaccines to include peptides from common human pathogens (such as EBV and human CMV) that are recognized by high frequency CD4 + T cells. Furthermore, the addition of exogenous CD4 + Th has been shown to rescue virus-specific CD8 + CTL function after chronic viral infection (52). Another approach would be to include vaccine conjugates or carriers, such as the diphtheria toxin cross-reactive material 197 as a carrier protein (53), or promiscuous T cell epitopes such as those derived from the fusion protein of the morbillivirus canine distemper virus (54) or tetanus toxin (55) that could also serve to activate pre-existing memory CD4 + T cells in a broader manner.…”