DRAK2 contributes to type 1 diabetes by negatively regulating IL-2 sensitivity to alter regulatory T cell development
Year: 2023
Type: article
Abstract: Drak2 -deficient ( Drak2 −/− ) mice are resistant to multiple models of autoimmunity yet effectively eliminate pathogens and tumors. Thus, DRAK2 represents a potential target to treat autoimmune diseases. However, the mechanisms by which DRAK2 contributes to autoimmunity, particularly type 1 diabetes (T1D), remain unresolved. Here, we demonstrate that resistance to T1D in non-obese diabetic ( NOD ) mice is due to the absence of Drak2 in T cells and requires the presence of regulatory T cells (T regs ). Contrary to previous hypotheses, we show that DRAK2 does not limit TCR signaling. Rather, DRAK2 regulates IL-2 signaling by inhibiting STAT5A phosphorylation. We further demonstrate that enhanced sensitivity to IL-2 in the absence of Drak2 augments thymic T reg development. Overall, our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic T reg development and by impacting the sensitivity of conventional T cells to T reg -mediated suppression.
Source: Cell Reports
Authors: Alexandra H. Mandarano, Tarsha L. Harris, Blaine M. Creasy, Marie Wehenkel, Marygrace Duggar, Benjamin A. Wilander, Ashutosh Mishra, Jeremy Chase Crawford, Sarah A. Mullen, Katherine M. Williams, Meenu Pillai, Anthony A. High, Maureen A. McGargill
Institution: St. Jude Children's Research Hospital
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,460
Funders: Juvenile Diabetes Research Foundation International, St. Jude Children's Research Hospital, Juvenile Diabetes Research Foundation United States of America, American Lebanese Syrian Associated Charities, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases
OpenAlex ID: W4320032769