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

RD Aubert, AO Kamphorst, S Sarkar… - Proceedings of the …, 2011 - National Acad Sciences
RD Aubert, AO Kamphorst, S Sarkar, V Vezys, SJ Ha, DL Barber, L Ye, AH Sharpe…
Proceedings of the National Academy of Sciences, 2011National Acad Sciences
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 …
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 virus-specific 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.
National Acad Sciences
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