Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo.
Autoreactive B lymphocytes first encountering self-antigens in peripheral tissues are normally regulated by induction of anergy or apoptosis. According to the "two-signal" model, antigen recognition alone should render B cells tolerant unless T cell help or inflammatory signals such as lipopolysaccharide are provided. However, no such signals seem necessary for responses to T-independent type 2 (TI-2) antigens, which are multimeric antigens lacking T cell epitopes and Toll-like receptor ligands. How then do mature B cells avoid making a TI-2-like response to multimeric self-antigens? We present evidence that TI-2 antigens decorated with ligands of inhibitory sialic acid-binding Ig-like lectins (siglecs) are poorly immunogenic and can induce tolerance to subsequent challenge with immunogenic antigen. Two siglecs, CD22 and Siglec-G, contributed to tolerance induction, preventing plasma cell differentiation or survival. Although mutations in CD22 and its signaling machinery have been associated with dysregulated B cell development and autoantibody production, previous analyses failed to identify a tolerance defect in antigen-specific mutant B cells. Our results support a role for siglecs in B cell self-/nonself-discrimination, namely suppressing responses to self-associated antigens while permitting rapid "missing self"-responses to unsialylated multimeric antigens. The results suggest use of siglec ligand antigen constructs as an approach for inducing tolerance.
Duong
Bao Hoa
BH
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Tian
Hua
H
Ota
Takayuki
T
Completo
Gladys
G
Han
Shoufa
S
Vela
José Luis
JL
Ota
Miyo
M
Kubitz
Michael
M
Bovin
Nicolai
N
Paulson
James C
JC
Paulson
James
J
Nemazee
David
D
D000818:Animals; D000917:Antibody Formation / Q000502:physiology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D037102:Lectins / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000235:genetics / Q000276:immunology*; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; C497868:Cd22 protein, mouse; D037102:Lectins; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; C522403:Siglecg protein, mouse