TY - JOUR
T1 - STAT4 Is Largely Dispensable for Systemic Lupus Erythematosus–like Autoimmune- And Foreign Antigen–Driven Antibody-Forming Cell, Germinal Center, and Follicular Th Cell Responses
AU - Fike, Adam J.
AU - Chodisetti, Sathi Babu
AU - Bricker, Kristen N.
AU - Choi, Nicholas M.
AU - Chroneos, Zissis C.
AU - Kaplan, Mark H.
AU - Rahman, Ziaur S.M.
N1 - Funding Information:
This work was supported by National Institutes of Health R21AI128111 to Z.S.M.R. and the American Association of Immunologists Careers in Immunology Fellowship and the Finkelstein Memorial award (both to A.J.F.). We thank the Pennsylvania State University Hershey Medical Center flow cytometry core facility for help with flow cytometric experiments. We would also like to thank the Pennsylvania State University Hershey Medical Center Department of Comparative Medicine for help with animal housing and care. We thank the support staff within the central facility of the Department of Microbiology and Immunology at Pennsylvania State College of Medicine.
Funding Information:
Received for publication December 14, 2020. Accepted for publication December 15, 2020. Address correspondence and reprint requests to: Dr. Ziaur S. M. Rahman, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033-0850. E-mail address: [email protected] ORCIDs: 0000-0001-8963-9780 (K.N.B.); 0000-0001-8431-9681 (Z.S.M.R.). This work was supported by National Institutes of Health R21AI128111 to Z.S.M.R. and the American Association of Immunologists Careers in Immunology Fellowship and the Finkelstein Memorial award (both to A.J.F.). Abbreviations used in this article: AFC, Ab-forming cell; ANA, antinuclear Ab; GC, germinal center; GWAS, genome-wide association study; IC, immune complex; IF, immunofluorescent; Imq, imiquimod; NP-KLH, 4-hydroxy-3-nitrophenol–keyhole limpet hemocyanin; SmRNP, small ribonucleoprotein; Spt, spontaneous; Tfh, T follicular helper cell. The online version of this article contains supplemental material. This article is distributed under the terms of the CC BY 4.0 Unported license. Copyright © 2021 The Authors
Publisher Copyright:
Copyright © 2021 The Authors
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Genome-wide association studies identified variants in the transcription factor STAT4 gene and several other genes in the STAT4 signaling pathway, such as IL12A, IL12B, JAK2, and TYK2, which are associated with an increased risk of developing systemic lupus erythematosus (SLE) and other autoimmune diseases. Consistent with the genome-wide association studies data, STAT4 was shown to play an important role in autoimmune responses and autoimmunity development in SLE mouse models. Despite such important role for STAT4 in SLE development in mice and humans, little is known whether and how STAT4 may regulate extrafollicular Ab-forming cell (AFC) and follicular germinal center (GC) responses, two major pathways of autoreactive B cell development and autoantibody production. To our surprise, we found STAT4 to be largely dispensable for promoting autoimmune AFC and GC responses in various autoimmune- and SLE-prone mouse models, which strongly correlated with autoantibody production, and immune complex deposition and immune cell infiltration in the kidney. We further observed that STAT4 deficiency had no effects on AFC, GC, and Ag-specific Ab responses during protein Ag immunization or influenza virus infection. Additionally, CD4+ effector and follicular Th cell responses in autoimmune- and SLE-prone mice and protein Ag–immunized and influenza virus–infected mice were intact in the absence of STAT4. Together, our data demonstrate a largely dispensable role for STAT4 in AFC, GC, and Ab responses in SLE mouse models and in certain foreign Ag–driven responses.
AB - Genome-wide association studies identified variants in the transcription factor STAT4 gene and several other genes in the STAT4 signaling pathway, such as IL12A, IL12B, JAK2, and TYK2, which are associated with an increased risk of developing systemic lupus erythematosus (SLE) and other autoimmune diseases. Consistent with the genome-wide association studies data, STAT4 was shown to play an important role in autoimmune responses and autoimmunity development in SLE mouse models. Despite such important role for STAT4 in SLE development in mice and humans, little is known whether and how STAT4 may regulate extrafollicular Ab-forming cell (AFC) and follicular germinal center (GC) responses, two major pathways of autoreactive B cell development and autoantibody production. To our surprise, we found STAT4 to be largely dispensable for promoting autoimmune AFC and GC responses in various autoimmune- and SLE-prone mouse models, which strongly correlated with autoantibody production, and immune complex deposition and immune cell infiltration in the kidney. We further observed that STAT4 deficiency had no effects on AFC, GC, and Ag-specific Ab responses during protein Ag immunization or influenza virus infection. Additionally, CD4+ effector and follicular Th cell responses in autoimmune- and SLE-prone mice and protein Ag–immunized and influenza virus–infected mice were intact in the absence of STAT4. Together, our data demonstrate a largely dispensable role for STAT4 in AFC, GC, and Ab responses in SLE mouse models and in certain foreign Ag–driven responses.
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U2 - 10.4049/immunohorizons.2000111
DO - 10.4049/immunohorizons.2000111
M3 - Article
C2 - 33446493
AN - SCOPUS:85115864141
SN - 2573-7732
VL - 5
SP - 2
EP - 15
JO - ImmunoHorizons
JF - ImmunoHorizons
IS - 1
ER -