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National Institute of Environmental Health Sciences

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Publication Detail

Title: Interleukin-2-inducible T-cell kinase (Itk) signaling regulates potent noncanonical regulatory T cells.

Authors: Mammadli, Mahinbanu; Harris, Rebecca; Suo, Liye; May, Adriana; Gentile, Teresa; Waickman, Adam T; Bah, Alaji; August, Avery; Nurmemmedov, Elmar; Karimi, Mobin

Published In Clin Transl Med, (2021 Dec)

Abstract: Regulatory T cells (Tregs) play an important role in controlling autoimmunity and limiting tissue damage and inflammation. IL2-inducible T cell kinase (Itk) is part of the Tec family of tyrosine kinases and is a critical component of T cell receptor mediated signaling. Here, we showed that either genetic ablation of Itk signaling or inhibition of Itk signaling pathways resulted in increased frequency of "noncanonical" CD4+ CD25- FOXP3+ Tregs (ncTregs), as well as of "canonical" CD4+ CD25+ FOXP3+ Tregs (canTregs). Using in vivo models, we showed that ncTregs can avert the formation of acute graft-versus-host disease (GVHD), in part by reducing conventional T cell proliferation, proinflammatory cytokine production, and tissue damage. This reduction in GVHD occurred without disruption of graft-versus-leukaemia (GVL) effects. RNA sequencing revealed that a number of effector, cell adhesion, and migration molecules were upregulated in Itk-/- ncTregs. Furthermore, disrupting the SLP76: ITK interaction using a specific peptide inhibitor led to enhanced Treg development in both mouse and primary human cells. This peptide inhibitor also significantly reduced inflammatory cytokine production in primary GVHD patient samples and mouse T cells without causing cell death or apoptosis. We provide evidence that specifically targeting Itk signaling could be a therapeutic strategy to treat autoimmune disorders.

PubMed ID: 34919342 Exiting the NIEHS site

MeSH Terms: Animals; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay/methods; Enzyme-Linked Immunosorbent Assay/statistics & numerical data; Erythrocytes/metabolism; Interleukin-2/metabolism; Interleukin-2/pharmacology*; Mice; Mice, Inbred C57BL/genetics; Mice, Inbred C57BL/metabolism; Signal Transduction/drug effects; T-Lymphocytes, Regulatory/drug effects*; T-Lymphocytes, Regulatory/physiology

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