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bioRxiv · 10.1101/386508

A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ Treg differentiation

Mamontov, P.·Eberwine, R. A.·Perrigoue, J.·Das, A.·Friedman, J. R.·Mora, J. R.
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Abstract

The Tec kinases ITK (interleukin-2-inducible T-cell kinase) and RLK (resting lymphocyte kinase) are critical components of the proximal TCR/CD3 signal transduction machinery, and data in mice suggest that ITK negatively regulates TREG differentiation. However, whether Tec kinases modulate TREG development and/or function in human T cells remains unknown. Using a novel self-delivery siRNA platform (sdRNA), we found that ITK knockdown in primary human naive peripheral blood CD4 T cells increased Foxp3+ TREG differentiation under both TREG and T effector (Teff) cell priming conditions. ITK knockdown also enhanced the expression of the co-inhibitory receptor PD-1 on FoxP3+ T cells. TREGS differentiated in vitro (iTREG) after ITK knockdown displayed suppressive capacity against effector CD4+ T cell proliferation. ITK knockdown decreased IL-17A production in T cells primed under Th17 conditions and increased Th1 differentiation. Finally, a dual ITK/RLK Tec kinase inhibitor blocked TREG differentiation and T cell activation in general. Our data suggest that targeting ITK in human T cells may be an effective approach to boost TREG in the context of autoimmune diseases, but non-specific inhibition of other Tec family kinases may broadly inhibit T cell activation.

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Mamontov, P., Eberwine, R. A., Perrigoue, J., Das, A., Friedman, J. R., Mora, J. R.. 2018-08-07. A negative role for the interleukin-2-inducible T-cell kinase (ITK) in human Foxp3+ Treg differentiation. https://doi.org/10.1101/386508

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