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

Abstract

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.

Characterization of age‐associated exhausted CD8+ T cells defined by increased expression of Tim‐3 and PD‐1

“…Notably, the expression of LAG‐3 on Tim‐3 + PD‐1 + cells was found to be significantly higher compared to Tim‐3 − PD‐1 + cells. Of interest, the expression of CD160 was opposite to what was observed in chronic infection‐induced exhausted cells (Blackburn et al ., 2009), which indicates that age‐related exhaustion is not identical to chronic infection‐induced exhaustion. Collectively, these results show that Tim‐3 + PD‐1 + and Tim‐3 − PD‐1 + CD8 + T cells in aged individuals display mostly similar exhausted phenotypes, but they are distinguishable from each other and from other types of exhausted cells based on some aspects of their surface molecule profiles.…”

“…To further characterize the exhausted phenotype of aged Tim‐3 + PD‐1 + CD8 + T cells, we next examined the expression of several surface molecules that were shown to be up‐ or down‐regulated in exhausted CD8 + T cells in a chronic infectious mouse model (Blackburn et al ., 2009). As a result, most of the exhaustion‐related molecules showed the same tendencies as those in the chronic infection model, and their expression levels were similar between aged Tim‐3 + PD‐1 + and Tim‐3 − PD‐1 + cells (Fig.…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…acute WE or Armstrong and chronic clone-13 or docile strains) facilitated in depth characterizations of how the duration of infections caused by very similar pathogens impacts T-cell differentiation. These studies prompted the discovery of the abovementioned chronic infection phenotype 15,24 and established that acquiring this phenotype and deletion of antigen-specific T-cells are in parallel or sequentially occurring events. Taking into count that T-cells which do not become deleted show a different phenotype, that they are difficult to re-expand in vitro, and that they do not survive well following adoptive transfer into antigen negative hosts 25 all this sustained the concept that the residual T-cells are non-functional -a notion that intuitively goes along with the inability of the immune-system to clear the virus.…”

“…A different outcome arises when infections become chronic and when viruses persist at high levels over long periods as in Human-Immunodeficiency-Virus (HIV) or Human-Hepatitis-C Virus (HCV) infections. Such conditions induce T-cells lacking the typical polyfunctional phenotype and T-cells retain the expression of inhibitory receptors including PD-1, Lag-3, Tim-3, and CD160 [9][10][11][12][13][14][15][16][17] . Very similar phenotypes can be observed, when T-cells are long-term exposed to tumor-antigen [18][19][20] .…”

T cells responding to Trypanosoma cruzi detected by membrane TNF‐α and CD154 in chagasic patients

“…Cytokine secretion can be limited by the T cell exhaustion state 12, 32 during chronic viral infections 33, 34, malignant tumors 35, and parasitic diseases 36. Chronic chagasic patients displayed dysfunctional T cell responses characterized by increased frequency of terminally differentiated cells, monofunctional antigen‐specific T cell responses and progressive attenuation of cytokine production 7, 10, 21, 37.…”