Distinct Roles for CXCR6⁺ and CXCR6⁻ CD4⁺ T Cells in the Pathogenesis of Chronic Colitis

<div><p>CD4⁺ T cells play a central role in the development of inflammatory bowel disease (IBD) via high-level production of effector cytokines such as IFN-γ and TNF-α. To better characterize the colitogenic CD4⁺ T cells, we examined their expression of CXCR6, a chemokine receptor that is expressed by T cells upon activation and is upregulated in several inflammatory diseases. We found that 80% of colonic lamina propria CD4⁺ T cells expressed CXCR6 in the CD45RB^high T cell-transferred colitis model. CXCR6 expression was similarly upregulated in inflamed mucosa of patients with Crohn’s disease. Although surface marker analysis demonstrated that both CXCR6⁺ and CXCR6⁻ CD4⁺ T-cell subsets consist of the cells with effector and effector-memory cells, the more cells in the CXCR6⁺ subset produced IFN-γ and TNF-α compared to CXCR6⁻ subset, and only the CXCR6⁺ subset produced IL-17A. Nevertheless, adoptive retransfer of lamina propria CXCR6⁺ T cells into <i>Rag1</i>^−/− recipients failed to induce the disease due to limited expansion of the transferred cells. By contrast, retransfer of CXCR6⁻ cells evoked colitis similar to that observed in CD4⁺CD45RB^high T cell-transferred mice, and resulted in their conversion into CXCR6⁺ cells. Collectively, these observations suggest that the CXCR6⁺CD4⁺ T-cell subset consists of terminally differentiated effector cells that serve as the major source of effector cytokines in the inflamed tissue, whereas CXCR6⁻CD4⁺ T-cell subset serves as a colitogenic memory compartment that retains the ability to proliferate and differentiate into CXCR6⁺CD4⁺ T cells.</p>