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 - Funding Information:
This work was supported by National Institutes of Health National Institutes of Allergy and Infectious Diseases RO1AI091670 (to Z.S.M.R.), Lupus Research Alliance Grant 548931 (to Z.S.M.R.), and the Finkelstein Memorial award (to S.B.C.). S.B.C. and Z.S.M.R. designed experiments. S.B.C. performed most of the experiments. A.J.F., P.P.D., N.M.C., T.E.M., and S.L.S. performed specific experiments. C.C., H.M.A., and R.C. evaluated the kidney pathology and performed glomerulonephritis scoring. T.D. provided S727A mice. B.H. provided VLPs. A.E.L. and N.O. helped in the discussion of designing specific experiments. S.B.C., A.J.F., and Z.S.M.R. wrote the manuscript. We thank the Penn State University Hershey Medical Center flow cytometry core facility for their assistance. We thank the Penn State University Hershey Medical Center Department of Comparative Medicine for animal housing and care.
Funding Information:
This work was supported by National Institutes of Health National Institutes of Allergy and Infectious Diseases RO1AI091670 (to Z.S.M.R.), Lupus Research Alliance Grant 548931 (to Z.S.M.R.), and the Finkelstein Memorial award (to S.B.C.).
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 -