TY - JOUR
T1 - STAT3 signaling in B cells controls germinal center zone organization and recycling
AU - Fike, Adam J.
AU - Chodisetti, Sathi Babu
AU - Wright, Nathaniel E.
AU - Bricker, Kristen N.
AU - Domeier, Phillip P.
AU - Maienschein-Cline, Mark
AU - Rosenfeld, Aaron M.
AU - Luckenbill, Sara A.
AU - Weber, Julia L.
AU - Choi, Nicholas M.
AU - Luning Prak, Eline T.
AU - Mandal, Malay
AU - Clark, Marcus R.
AU - Rahman, Ziaur S.M.
N1 - Funding Information:
We thank the Pennsylvania State University Hershey Medical Center (PSUHMC) flow cytometry core facility for help with experiments. We also thank the PSUHMC Department of Comparative Medicine for help with animal housing and care. We acknowledge the contribution of Vivian Gersuk and thank the Genomics Core at Benaroya Research Institute with their help with RNA-seq. Further, we thank Dr. Daisuke Kitamura for kindly providing the 40LB fibroblast cell line. Finally, we thank Drs. Zissis Chroneos for the influenza virus and Aron Lukacher for the critical reading of the manuscript. We used BioRender for the graphical abstract. This study was supported by the following grants: National Institutes of Health grants R01 AI162971 (ZSMR) , R01AI091670 (ZSMR) , R01AI143778 (MRC) ; Lupus Research Alliance Award 548931 (Z.S.M.R.) ; the Finkelstein Memorial Award (P.P.D.); National Cancer Institute 5T32CA060395-25 (A.J.F.) ; and National Center for Advancing Translational Sciences UL1TR002003 (M.M.) .
Funding Information:
We thank the Pennsylvania State University Hershey Medical Center (PSUHMC) flow cytometry core facility for help with experiments. We also thank the PSUHMC Department of Comparative Medicine for help with animal housing and care. We acknowledge the contribution of Vivian Gersuk and thank the Genomics Core at Benaroya Research Institute with their help with RNA-seq. Further, we thank Dr. Daisuke Kitamura for kindly providing the 40LB fibroblast cell line. Finally, we thank Drs. Zissis Chroneos for the influenza virus and Aron Lukacher for the critical reading of the manuscript. We used BioRender for the graphical abstract. This study was supported by the following grants: National Institutes of Health grants R01 AI162971 (ZSMR), R01AI091670 (ZSMR), R01AI143778 (MRC); Lupus Research Alliance Award 548931 (Z.S.M.R.); the Finkelstein Memorial Award (P.P.D.); National Cancer Institute 5T32CA060395-25 (A.J.F.); and National Center for Advancing Translational Sciences UL1TR002003 (M.M.). A.J.F. S.B.C. and Z.S.M.R. conceptualized and designed the experiments. A.J.F. S.B.C. K.N.B. J.L.W. S.A.L. N.M.C. N.E.W. and M.M. conducted the experiments under the supervision of Z.S.M.R. and A.J.F. and N.E.W. M.M. A.M.R. M.M. P.P.D. and E.T.L.P. analyzed the data. Z.S.M.R. and A.J.F. wrote the manuscript. Z.S.M.R. M.M.-C. M.M. P.P.D. and A.J.F. acquired funding. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/5/30
Y1 - 2023/5/30
N2 - Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we show a B cell-intrinsic role for signal transducer and activator of transcription 3 (STAT3) in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampens development of long-lived plasma cells (LL-PCs) but increases memory B cells (MBCs). In an abundant antigenic environment, achieved here by prime-boost immunization, STAT3 is not required for GC initiation, maintenance, or proliferation but is important for sustaining GC zonal organization by regulating GC B cell recycling. Th cell-derived signals drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, regulating their recycling into the DZ. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses identified STAT3 regulated genes that are critical for LZ cell recycling and transiting through DZ proliferation and differentiation phases. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of PCs, but negatively regulates MBC output.
AB - Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we show a B cell-intrinsic role for signal transducer and activator of transcription 3 (STAT3) in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampens development of long-lived plasma cells (LL-PCs) but increases memory B cells (MBCs). In an abundant antigenic environment, achieved here by prime-boost immunization, STAT3 is not required for GC initiation, maintenance, or proliferation but is important for sustaining GC zonal organization by regulating GC B cell recycling. Th cell-derived signals drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, regulating their recycling into the DZ. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses identified STAT3 regulated genes that are critical for LZ cell recycling and transiting through DZ proliferation and differentiation phases. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of PCs, but negatively regulates MBC output.
UR - https://www.scopus.com/pages/publications/85159389672
UR - https://www.scopus.com/pages/publications/85159389672#tab=citedBy
U2 - 10.1016/j.celrep.2023.112512
DO - 10.1016/j.celrep.2023.112512
M3 - Article
C2 - 37200190
AN - SCOPUS:85159389672
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 5
M1 - 112512
ER -