CCR9 Is Not Required for the Homing of Pro-inflammatory Effector T cells, but Is Crucial for Recruitment and Expansion of FoxP3+ CD8+ Tregs in the Small Intestine

Chemokine receptor 9 (CCR9) is required for the homeostatic recruitment of T cells to the mucosa of the small intestine. Accordingly, CCR9 has been suggested as a potential target to inhibit the recruitment of pro-inflammatory effector T cells (T_eff) in inflammatory bowel disease (IBD). Since the contribution of CCR9 to the recruitment of T_eff in inflammation is not entirely clear, we aimed to address this question using IFABP-tOva mice. These mice express Ovalbumin (Ova) specifically in small intestinal epithelial cells, which allows triggering of acute inflammation following transfer of Ova-specific CD8⁺ T cells (OT-I cells) and adjuvant treatment. Strikingly, intestinal inflammation in IFABP-tOva mice could also be triggered following transfer of CCR9-deficient OT-I cells, demonstrating that CCR9 is not required for homing of T_eff cells. Interestingly, OT-I cells transferred to IFABP-tOva mice did not only differentiate into T_eff, but also into FoxP3⁺ CD8⁺ Tregs, which in contrast to T_eff cells expressed high levels of CCR9. Indeed, recruitment and expansion of this regulatory subset in the small intestine was strongly dependent on CCR9. Hence, our data show that T_eff and regulatory T cell subsets use distinct mechanisms for migration to the small intestine and suggest that inhibition of CCR9 in IBD could be more harmful than useful.