CX3CR1: Re-Defining Exhausted CD8+ T Cell Populations

Abstract

Persistent infections result in dysfunctional state of CD8+ T cells associated with the expression of multiple inhibitory receptors. Recent studies have attempted to elucidate T cell subsets in chronic infections1–5. Similarly, the chemokine receptor CX3CR1 has been recently three effector and memory subsets6. Here, we show that CX3CR1 potentially identifies three subsets of exhausted CD8+ T cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). Preliminary data indicate a notable delay in the formation of the CX3CR1hi subset at the effector stage. The CX3CR1hi cells were localized to the blood while the CX3CR1- and CX3CR1int cells resided in the extravascular compartments. Phenotypically, the CX3CR1- subset was the predominant CXCR5+ Tim3- subset, while the CX3CR1hi cells were PD-1int. Higher cytokine production and degranulation were observed on the CX3CR1- followed by the CX3CR1int and CX3CR1hi subsets. Adoptive transfer of these subsets into naïve recipients showed that the CX3CR1- subset had the highest proliferative capacity while the CX3CR1hi cells barely proliferated. The CX3CR1int was intermediate in its expression levels of inhibitory receptors, cytokine production, cytotoxicity and proliferative capacity. Further validation of these results, along with studies assaying subset differences in their proliferative capacity, relative responsiveness to checkpoint inhibitors and ability to clear virus are currently ongoing.