TY - JOUR
T1 - Serine phosphorylation of the STAT1 transactivation domain promotes autoreactive B cell and systemic autoimmunity development
AU - Chodisetti, Sathi Babu
AU - Fike, Adam J.
AU - Domeier, Phillip P.
AU - Schell, Stephanie L.
AU - Mockus, Taryn E.
AU - Choi, Nicholas M.
AU - Corradetti, Chelsea
AU - Hou, Baidong
AU - Atkins, Hannah M.
AU - Caricchio, Roberto
AU - Decker, Thomas
AU - Lukacher, Aron E.
AU - Olsen, Nancy
AU - Rahman, Ziaur S.M.
N1 - Publisher Copyright:
Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved.
PY - 2020/5/15
Y1 - 2020/5/15
N2 - Although STAT1 tyrosine-701 phosphorylation (designated STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (designated STAT1-pS727) during systemic autoimmune and antipathogen responses remains unclear. Using autoimmune-prone B6.Sle1b mice expressing a STAT1-S727A mutant in which serine is replaced by alanine, we report in this study that STAT1-pS727 promotes autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, driving autoantibody production and systemic lupus erythematosus (SLE) development. In contrast, STAT1-pS727 is not required for GC, T follicular helper cell (Tfh), and Ab responses to various foreign Ags, including pathogens. STAT1-pS727 is also not required for gut microbiota and dietary Ag–driven GC and Tfh responses in B6.Sle1b mice. By generating B cell–specific bone marrow chimeras, we demonstrate that STAT1-pS727 plays an important B cell–intrinsic role in promoting autoimmune AFC, GC, and Tfh responses, leading to SLE-associated autoantibody production. Our analysis of the TLR7-accelerated B6.Sle1b.Yaa SLE disease model expressing a STAT1-S727A mutant reveals STAT1-pS727–mediated regulation of autoimmune AFC and GC responses and lupus nephritis development. Together, we identify previously unrecognized differential regulation of systemic autoimmune and antipathogen responses by STAT1-pS727. Our data implicate STAT1-pS727 as a therapeutic target for SLE without overtly affecting STAT1-mediated protection against pathogenic infections.
AB - Although STAT1 tyrosine-701 phosphorylation (designated STAT1-pY701) is indispensable for STAT1 function, the requirement for STAT1 serine-727 phosphorylation (designated STAT1-pS727) during systemic autoimmune and antipathogen responses remains unclear. Using autoimmune-prone B6.Sle1b mice expressing a STAT1-S727A mutant in which serine is replaced by alanine, we report in this study that STAT1-pS727 promotes autoimmune Ab-forming cell (AFC) and germinal center (GC) responses, driving autoantibody production and systemic lupus erythematosus (SLE) development. In contrast, STAT1-pS727 is not required for GC, T follicular helper cell (Tfh), and Ab responses to various foreign Ags, including pathogens. STAT1-pS727 is also not required for gut microbiota and dietary Ag–driven GC and Tfh responses in B6.Sle1b mice. By generating B cell–specific bone marrow chimeras, we demonstrate that STAT1-pS727 plays an important B cell–intrinsic role in promoting autoimmune AFC, GC, and Tfh responses, leading to SLE-associated autoantibody production. Our analysis of the TLR7-accelerated B6.Sle1b.Yaa SLE disease model expressing a STAT1-S727A mutant reveals STAT1-pS727–mediated regulation of autoimmune AFC and GC responses and lupus nephritis development. Together, we identify previously unrecognized differential regulation of systemic autoimmune and antipathogen responses by STAT1-pS727. Our data implicate STAT1-pS727 as a therapeutic target for SLE without overtly affecting STAT1-mediated protection against pathogenic infections.
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U2 - 10.4049/jimmunol.2000170
DO - 10.4049/jimmunol.2000170
M3 - Article
C2 - 32253245
AN - SCOPUS:85084399711
SN - 0022-1767
VL - 204
SP - 2641
EP - 2650
JO - Journal of Immunology
JF - Journal of Immunology
IS - 10
ER -