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

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.