Cho, Hyoung-SooShin, HyunMuHaberstock-Debic, HelenaXing, YanOwens, Timothy D.Funk, Jens Oliver.Hill, Ronald J.Bradshaw, J. MichaelBerg, Leslie J.2022-08-232022-08-232015-11-152016-01-15J Immunol. 2015 Nov 15;195(10):4822-31. doi: 10.4049/jimmunol.1501828. <a href="http://dx.doi.org/10.4049/jimmunol.1501828">Link to article on publisher's site</a>.Epub 2015 Oct 14.0022-1767 (Linking)10.4049/jimmunol.150182826466958https://hdl.handle.net/20.500.14038/39867In 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.en-US<p>This article is distributed and freely available online under The American Association of Immunologists, Inc., <a href="http://www.jimmunol.org/site/misc/authorchoice.xhtml">Reuse Terms and Conditions for Author Choice articles</a>.</p>Digestive System DiseasesImmunityImmunopathologyMedical ImmunologyPathologyJournal Articlehttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3671&amp;context=oapubs&amp;unstamped=1https://escholarship.umassmed.edu/oapubs/26678015318oapubs/2667