Krüppel‐like factor 4 (KLF4) directly regulates proliferation in thymocyte development and IL‐17 expression during Th17 differentiation

Krüppel‐like factor 4 (KLF4), a transcription factor, plays a key role in the pluripotency of stem cells. We sought to determine the function of KLF4 in T‐cell development and differentiation by using T‐cell‐specific Klf4 ‐knockout (KO) mice. We found that KLF4 was highly expressed in thymocytes and mature T cells and was rapidly down‐regulated in mature T cells after activation. In Klf4‐KO mice, we observed a modest reduction of thymocytes (27%) due to the reduced proliferation of double‐negative (DN) thymocytes. We demonstrated that a direct repression of Cdkn1b by KLF4 was a cause of decreased DN proliferation. During in vitro T‐cell differentiation, we observed significant reduction of IL‐17‐expressing CD4 + T cells (Th17; 24%) but not in other types of Th differentiation. The reduction of Th17 cells resulted in a significant attenuation of the severity (35%) of experimental autoimmune encephalomyelitis in vivo in Klf4‐KO mice as compared with the Klf4 wild‐type littermates. Finally, we demonstrated that KLF4 directly binds to the promoter of Il17a and positively regulates its expression. In summary, these findings identify KLF4 as a critical regulator in T‐cell development and Th17 differentiation.—An, J., Golech, S., Klaewsongkram, J., Zhang, Y., Subedi, K., Huston, G. E., Wood, W. H., III, Wersto, R. P., Becker, K. G., Swain, S. L., Weng, N. Krüppel‐like factor 4 (KLF4) directly regulates proliferation in thymocyte development and IL‐17 expression during Th17 differentiation. FASEB J. 25, 3634–3645 (2011). www.fasebj.org