TY - JOUR
T1 - Functional characterization of CD11c+ age-associated B cells as memory B cells
AU - Du, Samuel W.
AU - Arkatkar, Tanvi
AU - Al Qureshah, Fahd
AU - Jacobs, Holly M.
AU - Thouvenel, Christopher D.
AU - Chiang, Kristy
AU - Largent, Andrea D.
AU - Li, Quan Zhen
AU - Hou, Baidong
AU - Rawlings, David J.
AU - Jackson, Shaun W.
N1 - Funding Information:
This work was supported by the National Institutes of Health under award numbers P01HL053749-21A1 (to D.J.R.), DP3DK111802 (to D.J.R.), R21AI123818 (to D.J.R.), K08AI112993 (to S.W.J.), and R01AR073938 (to S.W.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support provided by the Benar-oya Family Gift Fund (to D.J.R.), by the American College of Rheumatology (ACR) Research and Education Fund Rheumatology Scientist Development Award (to S.W.J.), by the ACR Rheumatology Research Foundation Career Development K Supplement (to S.W.J.), by the Arthritis National Research Foundation Eng Tan Scholar Award (to S.W.J.), by a Lupus Research Alliance Novel Research Grant (to S.W.J.), and by the University of Washington Arnold Lee Smith Endowed Professorship for Research Faculty Development (to S.W.J.).
Publisher Copyright:
© 2019 by The American Association of Immunologists, Inc.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Age-associated B cells (ABCs) are a unique subset of B cells defined by surface CD11b and CD11c expression. Although ABC expansion has been observed in both human and animal studies in the setting of advanced age, during humoral autoimmunity and following viral infection, the functional properties of this cellular subset remain incompletely defined. In the current study, we demonstrate that ABCs fulfill the criteria for memory B cells (MBCs), based on evidence of Ag-dependent expansion and persistence in a state poised for rapid differentiation into Ab-secreting plasma cells during secondary responses. First, we show that a majority of ABCs are not actively cycling but exhibit an extensive replication history consistent with prior Ag engagement. Second, despite unswitched surface IgM expression, ABCs show evidence of activation-induced cytidine deaminase (AID)-dependent somatic hypermutation. Third, BCRs cloned from sorted ABCs exhibit broad autoreactivity and polyreactivity. Although the overall level of ABC self-reactivity was not increased relative to naive B cells, ABCs lacked features of functional anergy characteristic of autoreactive B cells. Fourth, ABCs express MBC surface markers consistent with being poised for rapid plasma cell differentiation during recall responses. Finally, in a murine model of viral infection, adoptively transferred CD11c+ B cells rapidly differentiated into class-switched Ab-secreting cells upon Ag rechallenge. In summary, we phenotypically and functionally characterize ABCs as IgM-expressing MBCs, findings that together implicate ABCs in the pathogenesis of systemic autoimmunity.
AB - Age-associated B cells (ABCs) are a unique subset of B cells defined by surface CD11b and CD11c expression. Although ABC expansion has been observed in both human and animal studies in the setting of advanced age, during humoral autoimmunity and following viral infection, the functional properties of this cellular subset remain incompletely defined. In the current study, we demonstrate that ABCs fulfill the criteria for memory B cells (MBCs), based on evidence of Ag-dependent expansion and persistence in a state poised for rapid differentiation into Ab-secreting plasma cells during secondary responses. First, we show that a majority of ABCs are not actively cycling but exhibit an extensive replication history consistent with prior Ag engagement. Second, despite unswitched surface IgM expression, ABCs show evidence of activation-induced cytidine deaminase (AID)-dependent somatic hypermutation. Third, BCRs cloned from sorted ABCs exhibit broad autoreactivity and polyreactivity. Although the overall level of ABC self-reactivity was not increased relative to naive B cells, ABCs lacked features of functional anergy characteristic of autoreactive B cells. Fourth, ABCs express MBC surface markers consistent with being poised for rapid plasma cell differentiation during recall responses. Finally, in a murine model of viral infection, adoptively transferred CD11c+ B cells rapidly differentiated into class-switched Ab-secreting cells upon Ag rechallenge. In summary, we phenotypically and functionally characterize ABCs as IgM-expressing MBCs, findings that together implicate ABCs in the pathogenesis of systemic autoimmunity.
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U2 - 10.4049/jimmunol.1900404
DO - 10.4049/jimmunol.1900404
M3 - Article
C2 - 31636237
AN - SCOPUS:85075221088
SN - 0022-1767
VL - 203
SP - 2817
EP - 2826
JO - Journal of Immunology
JF - Journal of Immunology
IS - 11
ER -