CD4 + T‐Cell‐Intrinsic IL‐6 Is Critical for Th17 Differentiation and Dampened Responsiveness to CD8 + T Cell‐Mediated Suppression

ABSTRACT This study investigates the role of T‐cell‐intrinsic IL‐6 in Th17 differentiation and effector resistance. Using CRISPR‐Cas9‐mediated Il6 knockdown in primary human CD4 + T‐cells, we demonstrate that T‐cell‐produced IL‐6 is crucial for the optimal development of Th17 cells. Lack of T‐cell‐endogenous Il6 resulted in impaired IL‐17A production as well as significantly increased responsiveness to immune suppression. Importantly, these effects could not be reversed by the addition of exogenous IL‐6, likely due to interference with Il6R expression in the absence of endogenous Il6 , with consequent reduction in STAT3 phosphorylation. Blockade of IL‐6 receptor replicated the functional effects of Il6 knockdown and revealed a feedback loop between Il6 and Il6R expression. Of note, IL‐21 was able to bypass the need for IL‐6 in both Th17 differentiation and the development of resistance. Our findings emphasize T‐cell‐endogenous IL‐6 as a critical cytokine in Th17 cell biology and highlight IL‐6 and IL‐21 as potential immunotherapeutic targets.