ReviewCXCR3 in T cell function
Introduction
During the course of an immune response distinct functional subsets of effector and regulatory T cells are generated in the lymphoid compartment following the differentiation of naïve T cells under the influence of specific cytokines. CD4+ effector subsets include type-1 helper (Th1), Th2 and Th17, which are characterized by the production of different inflammatory cytokines to drive immunity and T regulatory cells (Tregs), which counterbalance these responses. Similar to Th1 cells that produce large amounts of interferon-gamma (IFNγ), CD8+ T cells can differentiate to become cytotoxic lymphocytes (CTLs), which secrete IFNγ along with other effector molecules. Once differentiated, these T cell subsets upregulate chemokine receptors, which guide them out of the lymphoid compartment and into sites of inflammation or infection to deliver an adaptive immune response. Effector T cell subsets differ profoundly in their migratory properties [1]. The induction of Th1 and CTL cells is strongly linked to the upregulation of the chemokine receptor CXCR3. CXCR3 binds three chemokines CXCL9 (also known as MIG, monokine induced by gamma-interferon), CXCL10 (IP-10, interferon-induced protein of 10 kDa), CXCL11 (I-TAC, interferon-inducible T cell alpha chemoattractant) to induce migration of activated T cells in vitro and in vivo [2], [3], [4], [5], [6]. CXCR3 and its ligands are undoubtedly an inflammatory chemokine system, capable of coordinating T cell responses in the inflamed periphery. In addition, this system may also play a role in the generation of both inflammatory and suppressive T cell responses.
While this review will focus exclusively on the role of CXCR3 on effector CD4+ and CD8+ T cells, it is also worth noting that CXCR3 is also highly expressed on innate lymphocytes, such as NK cells and NKT cells, where CXCR3 is thought to participate in the localization of these first line defenders at sites of infection and inflammation [7], [8]. Further, CXCR3 is expressed on plasmacytoid dendritic cells (DCs) and subsets of B cells where it may play a role in the migration of these cells in the inflamed lymph node (LN) [9], [10].
Section snippets
CXCR3—the inflammatory T cell chemokine receptor
Early studies found that T cells recovered from inflamed peripheral tissue in human autoimmune disease were highly enriched in CXCR3 surface expression relative to T cells found in the blood [7], [11], [12]. In addition, CXCR3 ligands were also found to be highly expressed in these same diseased tissues where CXCR3 positive T cells had accumulated (Table 1). These observations indicated a specific role for CXCR3 and its ligands in the recruitment of T cells into these otherwise restricted
Breaking the inflammatory loop—a role for CXCR3+ T regulatory cells
Although strong Th1 and CTL responses are beneficial during infection, these responses must be counterbalanced to prevent unwanted tissue destruction and immunopathology. Indeed, as detailed above, the identification of CXCR3+ Th1 cells was originally characterized in the affected tissues of patients with autoimmune arthritis and many autoimmune diseases are thought to result from deregulated Th1 responses. The induction of (Tregs) expressing the transcription factor FOXP3 is important for
CXCR3 in the induction and recall of immune responses
It is well established that CXCR3 expression by effector and regulatory T cells allows these cells entry into inflamed peripheral tissues. By contrast, the requirements for CXCR3 and its ligands during primary and secondary responses in the LN remain incompletely studied. Indeed, the use of in vitro activated effector cell transfer models in order to specifically investigate events in peripheral tissue has avoided scrutiny of the potential importance of CXCR3 during CD4+ and CD8+ T cell
Concluding comments and future directions
In the past few years much has been learned of the involvement of the CXCR3 chemokine system during inflammation. These studies have highlighted the role for CXCR3-dependent interactions in the coordination of inflammatory events in the periphery, both to increase recruitment of CD4+ and CD8+ effector T lymphocytes to drive inflammation, but also perhaps for the induction and recruitment of Th1-specific T regulatory cells to dampen over-exuberant responses. How CXCR3 balances the choice between
Acknowledgments
JRG was supported by Australian Government National Health and Medical Research Counsel and Overseas Biomedical Based Fellowship and ADL was supported by NIH grant CA69212.
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