Coregulation of CD8(+) T cell exhaustion during chronic viral infection by multiple inhibitory receptors

T cell exhaustion often occurs during chronic infections and prevents optimal viral control. The molecular pathways involved in T cell exhaustion, however, remain poorly understood. We demonstrate that exhausted CD8(+) T cells are subject to complex layers of negative regulation due to co-expression of multiple inhibitory receptors. Exhausted CD8(+) T cells expressed up to 7 inhibitory receptors. Co-expression of multiple distinct inhibitory receptors correlated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by diverse inhibitory pathways was non-redundant since blockade of PD-1 and LAG-3 simultaneously in vivo synergistically improved T cell responses and reduced viral load. Thus, CD8(+) T cell responses during chronic viral infections are regulated by complex patterns of co-expressed inhibitory receptors.