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Open Access Publications from the University of California

Chemokine receptor CXCR3 affects the balance between effector and memory CD8 T-cell generation

  • Author(s): Hu, Joyce
  • Advisor(s): Cyster, Jason
  • et al.
Abstract

During infection, pathogen-specific T cells must efficiently recognize their cognate antigen, expand into effector cells, and form memory cells that provide protection during subsequent encounters with the same pathogen. Chemokines and chemokine receptors play essential roles in these processes. They mediate T cell surveillance of antigens in secondary lymphoid organs (SLOs) and facilitate T cell contacts with other immune cells that result in activation, expansion into effector cells, and formation of functional memory cells. Within the spleen, activated CD8 T cells move from distinct compartments of the white pulp (WP) to the marginal zone (MZ) and red pulp (RP), where they exit the spleen and migrate to inflamed tissues. The molecular cues that guide activated CD8 T cells to splenic compartments and the effect of these movements on T cell differentiation are not completely understood. The chemokine receptor CXCR3 is expressed on activated CD8 T cells and guides these cells towards the interferon-inducible chemokines CXCL9, CXCL10, and CXCL11. We used wild-type (WT) and CXCR3 knock-out (KO) T cell receptor (TCR) transgenic P14 CD8 T cells to determine if CXCR3 directs activated CD8 T cells to specific splenic compartments and if CXCR3-directed movements influence CD8 T cell differentiation. Using lymphocytic choriomeningitis virus (LCMV) infection, we found that CXCR3 directed activated CD8 T cells towards CXCR3 ligands in the MZ, where LCMV antigens were abundant. In contrast, CXCR3 KO CD8 T cells were concentrated in the T zone away from antigen in the MZ. Because antigen and inflammation promote the generation of short-lived effector cells, we examined whether CXCR3-mediated positioning affected CD8 T cell differentiation. CD8 T cell clustering in the MZ was associated with increased generation of short-lived effector cells and decreased formation of memory precursor cells. This led to the generation of fewer memory cells that were phenotypically and qualitatively different. These data demonstrate that CXCR3 increases CD8 T cell access to antigen and potentially inflammation in the MZ that affects the balance between effector and memory cell generation.

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