Chemokine receptor CXCR3 facilitates CD8 ⁺ T cell differentiation into short-lived effector cells leading to memory degeneration

Abstract

CXCR3 regulates CD8 ⁺ T cell recruitment to sites of inflammation, thus dictating CD8 ⁺ T cell contraction and subsequent effector/memory cell fate.

Abstract

Strength of inflammatory stimuli during the early expansion phase plays a crucial role in the effector versus memory cell fate decision of CD8 ⁺ T cells. But it is not known how early lymphocyte distribution after infection has an impact on this process. We demonstrate that the chemokine receptor CXCR3 is involved in promoting CD8 ⁺ T cell commitment to an effector fate rather than a memory fate by regulating T cell recruitment to an antigen/inflammation site. After systemic viral or bacterial infection, the contraction of CXCR3 ^−/− antigen-specific CD8 ⁺ T cells is significantly attenuated, resulting in massive accumulation of fully functional memory CD8 ⁺ T cells. Early after infection, CXCR3 ^−/− antigen-specific CD8 ⁺ T cells fail to cluster at the marginal zone in the spleen where inflammatory cytokines such as IL-12 and IFN-α are abundant, thus receiving relatively weak inflammatory stimuli. Consequently, CXCR3 ^−/− CD8 ⁺ T cells exhibit transient expression of CD25 and preferentially differentiate into memory precursor effector cells as compared with wild-type CD8 ⁺ T cells. This series of events has important implications for development of vaccination strategies to generate increased numbers of antigen-specific memory CD8 ⁺ T cells via inhibition of CXCR3-mediated T cell migration to inflamed microenvironments.