CXCR3 in T cell function

Abstract

CXCR3 is a chemokine receptor that is highly expressed on effector T cells and plays an important role in T cell trafficking and function. CXCR3 is rapidly induced on naïve cells following activation and preferentially remains highly expressed on Th1-type CD4(+) T cells and effector CD8(+) T cells. CXCR3 is activated by three interferon-inducible ligands CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC). Early studies demonstrated a role for CXCR3 in the trafficking of Th1 and CD8 T cells to peripheral sites of Th1-type inflammation and the establishment of a Th1 amplification loop mediated by IFNγ and the IFNγ-inducible CXCR3 ligands. More recent studies have also suggested that CXCR3 plays a role in the migration of T cells in the microenvironment of the peripheral tissue and lymphoid compartment, facilitating the interaction of T cells with antigen presenting cells leading to the generation of effector and memory cells.

Figure 1. Model for Interferon-CXCR3 chemokine ligand-dependent inflammatory amplification in the periphery

This model describes the sequential events from left (1) to right (7) involving Type I and Type II interferon and the CXCR3 ligands, CXCL9 and CXCL10, in the initiation, amplification and resolution of Th1-type inflammation in the periphery. Open arrowheads indicate cytokine/chemokine secretion and closed arrowheads indicate cellular movements.

1. Initial innate challenge, such as bacterial or viral infection, activates TLRs and RNA helicases leading to the release of IFNα/β and subsequent secretion of chemokines, predominantly CXCL10.

2. CXCL10 recruits CD4+ Th1 cells and possibly NK cells into the target tissue.

3. DCs in the tissue present antigen to CD4+ Th1 cells, which in turn secrete IFNγ.

4. Tissue resident DCs and other cells take up IFNγ leading to secretion of CXCL9 and CXCL10.

5. CXCL9 and CXCL10 recruit CD8+ CTLs into the tissue

6. Migrated CD8+ CTLs secrete IFNγ, further stimulating tissue resident cells to produce more CXCL9 and CXCL10.

7. Increased chemokine release amplifies inflammation, leading to further recruitment of CXCR3-expressing Th1 T cells and CTLs.

8. Increased inflammation can also attract in CTLs in a CXCR3-independent manner.

9. CXCR3-expressing CD4+ Treg cells may also enter the tissue, to counterbalance the CTL and Th1 cell response and lead to resolution of Th1 inflammation.