A Small Molecule Inhibitor of ITK and RLK Impairs Th1 Differentiation and Prevents Colitis Disease Progression

J Immunol. 2015 Nov 15;195(10):4822-31. doi: 10.4049/jimmunol.1501828. Epub 2015 Oct 14.

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-γ 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Chemokine CCL20 / genetics
  • Chemokine CCL20 / immunology
  • Chemokine CXCL11 / genetics
  • Chemokine CXCL11 / immunology
  • Colitis / genetics
  • Colitis / immunology
  • Colitis / pathology
  • Colitis / prevention & control*
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Mice
  • Mice, Knockout
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / immunology*
  • Th1 Cells / immunology*
  • Th1 Cells / pathology
  • Th17 Cells / immunology
  • Th17 Cells / pathology

Substances

  • CCL20 protein, mouse
  • Chemokine CCL20
  • Chemokine CXCL11
  • Cxcl11 protein, mouse
  • Protein Kinase Inhibitors
  • Interferon-gamma
  • Tec protein-tyrosine kinase
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase