UMMS Affiliation

Department of Pathology

Date

11-15-2015

Document Type

Article

Disciplines

Digestive System Diseases | Immunity | Immunopathology | Medical Immunology | Pathology

Abstract

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.

Rights and Permissions

Citation: 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.

DOI of Published Version

10.4049/jimmunol.1501828

Comments

This article is distributed and freely available online under The American Association of Immunologists, Inc., Reuse Terms and Conditions for Author Choice articles.

Related Resources

Link to Article in PubMed

Journal Title

Journal of immunology (Baltimore, Md. : 1950)

PubMed ID

26466958

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