DRAK2 contributes to type 1 diabetes by negatively regulating IL-2 sensitivity to alter regulatory T cell development
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
Affiliations
Alexandra H. Mandarano
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Tarsha L. Harris
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Blaine M. Creasy
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Marie Wehenkel
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Marygrace Duggar
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; St. Jude Graduate School of Biomedical Sciences, Memphis, TN 38105, USA
Benjamin A. Wilander
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; St. Jude Graduate School of Biomedical Sciences, Memphis, TN 38105, USA
Ashutosh Mishra
Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Jeremy Chase Crawford
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Sarah A. Mullen
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Katherine M. Williams
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Meenu Pillai
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Anthony A. High
Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
Maureen A. McGargill
Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA; Corresponding author
Summary: 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 (Tregs). 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 Treg development. Overall, our data indicate that DRAK2 contributes to autoimmunity in multiple ways by regulating thymic Treg development and by impacting the sensitivity of conventional T cells to Treg-mediated suppression.
