Journal article
CD4+ T‐Cell‐Intrinsic IL‐6 Is Critical for Th17 Differentiation and Dampened Responsiveness to CD8+ T Cell‐Mediated Suppression
European journal of immunology, Vol.56(2), e70150
02/01/2026
DOI: 10.1002/eji.70150
PMCID: PMC12929703
PMID: 41731643
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. 1. Normal state: T‐cell‐endogenous IL‐6 stabilizes IL6R and promotes STAT3 activation, functional Th17 differentiation with resistance to immune suppression. 2. Il6‐KO: Loss of T‐cell endogenous IL‐6 destabilizes IL6R expression, leading to suboptimal Th17 and greater susceptibility to suppression, despite availability of exogenous IL‐6. 3. IL‐21 bypasses the requirement for endogenous IL‐6 by restoring STAT3 signaling and fully rescuing Th17 differentiation and effector resistance.
Details
- Title: Subtitle
- CD4+ T‐Cell‐Intrinsic IL‐6 Is Critical for Th17 Differentiation and Dampened Responsiveness to CD8+ T Cell‐Mediated Suppression
- Creators
- Chakrapani Vemulawada - University of IowaKshitija Kale - University of IowaMichael P. Crawford - University of IowaNitin J. Karandikar - University of Iowa Health Care and Iowa City VA Medical Center
- Resource Type
- Journal article
- Publication Details
- European journal of immunology, Vol.56(2), e70150
- DOI
- 10.1002/eji.70150
- PMID
- 41731643
- PMCID
- PMC12929703
- NLM abbreviation
- Eur J Immunol
- ISSN
- 0014-2980
- eISSN
- 1521-4141
- Publisher
- Wiley; WEINHEIM
- Grant note
- U.S. Department of Veterans Affairs: I01 CX002319
This work was supported, in part, by a grant award to N.J.K. from the U.S. Department of Veterans Affairs (I01 CX002319). The authors thank Drs. Alexander Boyden and Ashutosh K. Mangalam and their groups for insightful discussions and guidance.
- Language
- English
- Date published
- 02/01/2026
- Academic Unit
- Pathology
- Record Identifier
- 9985139478802771
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