Department of Pathology
Digestive System Diseases | Immunity | Immunopathology | Medical Immunology | Pathology
In T cells, the Tec kinases IL-2-inducible T cell kinase (ITK) and resting lymphocyte kinase (RLK) are activated by TCR stimulation and are required for optimal downstream signaling. Studies of CD4(+) T cells from Itk(-/-) and Itk(-/-)Rlk(-/-) mice have indicated differential roles of ITK and RLK in Th1, Th2, and Th17 differentiation and cytokine production. However, these findings are confounded by the complex T cell developmental defects in these mice. In this study, we examine the consequences of ITK and RLK inhibition using a highly selective and potent small molecule covalent inhibitor PRN694. In vitro Th polarization experiments indicate that PRN694 is a potent inhibitor of Th1 and Th17 differentiation and cytokine production. Using a T cell adoptive transfer model of colitis, we find that in vivo administration of PRN694 markedly reduces disease progression, T cell infiltration into the intestinal lamina propria, and IFN-gamma production by colitogenic CD4(+) T cells. Consistent with these findings, Th1 and Th17 cells differentiated in the presence of PRN694 show reduced P-selectin binding and impaired migration to CXCL11 and CCL20, respectively. Taken together, these data indicate that ITK plus RLK inhibition may have therapeutic potential in Th1-mediated inflammatory diseases.
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DOI of Published Version
J Immunol. 2015 Nov 15;195(10):4822-31. doi: 10.4049/jimmunol.1501828. Link to article on publisher's site.Epub 2015 Oct 14.
Journal of immunology (Baltimore, Md. : 1950)
Cho, Hyoung-Soo; Shin, HyunMu; Haberstock-Debic, Helena; Xing, Yan; Owens, Timothy D.; Funk, Jens Oliver.; Hill, Ronald J.; Bradshaw, J. Michael; and Berg, Leslie J., "A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression" (2015). Open Access Articles. 2667.