Expression of chemokine receptor CXCR3 on T cells affects the balance between effector and memory CD8 T-cell generation

Abstract

Generation of a robust immunological memory response is essential for protection on subsequent encounters with the same pathogen. The magnitude and quality of the memory CD8 T-cell population are shaped and influenced by the strength and duration of the initial antigenic stimulus as well as by inflammatory cytokines. Although chemokine receptors have been established to play a role in recruitment of effector CD8 T cells to sites of inflammation, their contribution to determination of T-cell fate and shaping of the long-lived memory T-cell population is not fully understood. Here, we investigated whether reduced access to antigen and inflammation through alterations in expression of inflammatory and homeostatic chemokine receptors has an impact on generation of effector and memory CD8 T cells. We found that in mice infected with lymphocytic choriomeningitis virus, colocalization of virus-specific CD8 T cells with antigen in spleen is dependent on expression of the inflammatory chemokine receptor, CXCR3. In addition, absence of CXCR3 expression on CD8 T cells leads to formation of fewer short-lived effector cells and more memory precursor cells. Furthermore, the memory CD8 T-cell population derived from CXCR3-deficient cells has fewer cells of the effector memory phenotype and exhibits a recall response of greater magnitude than that of WT cells. These data demonstrate that CD8 T-cell positioning relative to antigen and inflammatory cytokines in secondary lymphoid organs affects the balance of effector and memory T-cell formation and has both a quantitative and qualitative impact on the long-lived memory CD8 T-cell population.microenvironment | T-cell differentiation | trafficking

CD8+ T Cells Produce the Chemokine CXCL10 in Response to CD27/CD70 Costimulation To Promote Generation of the CD8+ Effector T Cell Pool

“…This redistribution was impaired when the CD8 + T cells lacked expression of CXCR3. It was suggested that this redistribution within the priming organ and the consequent longer or shorter contact with Ag-presenting DCs determined the long-term fate of the CD8 + T cells (51,52). Our data are in full agreement with the concept that CXCR3 and CXCL10 play a role in the localization of primed CD8 + T cells at the site of priming and, thereby, affect the CD8 + T cell response.…”

“…We now add that CXCL10 performs such a function for CD8 + T cells, in accordance with a recent finding that CXCL10 produced by DCs can support the generation of a CD8 + T cell response (50). Interestingly, recent findings on the role of CXCR3 in fate determination of primed CD8 + T cells further support this notion (51,52). CXCR3 binds CXCL9, CXCL10, and CXCL11, but C57BL/6 mice only express CXCL9 and CXCL10 (52).…”

“…Interestingly, recent findings on the role of CXCR3 in fate determination of primed CD8 + T cells further support this notion (51,52). CXCR3 binds CXCL9, CXCL10, and CXCL11, but C57BL/6 mice only express CXCL9 and CXCL10 (52). Therefore, findings on CXCR3 function in C57BL/6 mice reflect the role of one or both of these chemokines.…”

“…Therefore, findings on CXCR3 function in C57BL/6 mice reflect the role of one or both of these chemokines. Kurachi et al (51) and Hu et al (52) found that CXCR3 on CD8 + T cells promoted their commitment to an effector fate, rather than a memory fate. Both studies used acute infection with a systemic virus and monitored CD8 + T cell responses in the spleen.…”

Regulation of Tissue-Dependent Differences in CD8+T Cell Apoptosis during Viral Infection

“…CD27-CD70 interactions have been shown to induce autocrine IL-2 production in CD8 ϩ T cells, thereby promoting their survival (18). Activated T cells may also express CXCR3, a chemokine receptor required for T cell chemotaxis to the site of antigen (19,20). Moreover, individual expression of IL-7R, CD27, and CXCR3 has been used to identify memory CD8 ϩ T cell populations with an efficient recall response (21).…”