CD22 Promotes B-1b Cell Responses to T Cell–Independent Type 2 Antigens

Abstract

CD22 (Siglec-2) is a critical regulator of B cell activation and survival. CD22 mice generate significantly impaired Ab responses to T cell-independent type 2 (TI-2) Ags, including haptenated Ficoll and pneumococcal polysaccharides, Ags that elicit poor T cell help and activate BCR signaling via multivalent epitope crosslinking. This has been proposed to be due to impaired marginal zone (MZ) B cell development/maintenance in CD22 mice. However, mice expressing a mutant form of CD22 unable to bind sialic acid ligands generated normal TI-2 Ab responses, despite significantly reduced MZ B cells. Moreover, mice treated with CD22 ligand-binding blocking mAbs, which deplete MZ B cells, had little effect on TI-2 Ab responses. We therefore investigated the effects of CD22 deficiency on B-1b cells, an innate-like B cell population that plays a key role in TI-2 Ab responses. B-1b cells from CD22 mice had impaired BCR-induced proliferation and significantly increased intracellular Ca concentration responses following BCR crosslinking. Ag-specific B-1b cell expansion and plasmablast differentiation following TI-2 Ag immunization was significantly impaired in CD22 mice, consistent with reduced TI-2 Ab responses. We generated CD22 mice with reduced CD19 levels (CD22CD19) to test the hypothesis that augmented B-1b cell BCR signaling in CD22 mice contributes to impaired TI-2 Ab responses. BCR-induced proliferation and intracellular Ca concentration responses were normalized in CD22CD19 B-1b cells. Consistent with this, TI-2 Ag-specific B-1b cell expansion, plasmablast differentiation, survival, and Ab responses were rescued in CD22CD19 mice. Thus, CD22 plays a critical role in regulating TI-2 Ab responses through regulating B-1b cell signaling thresholds.

The B-cell inhibitory receptor CD22 is a major factor in host resistance to Streptococcus pneumoniae infection

“…The role of CD22 in immune responses previously has been studied with different classes of model antigens. Although thymus-independent antibody responses of CD22-deficient mice to antigens, such as NP-ficoll, are impaired due to missing or non-functional B cell subpopulations, such as marginal zone (MZ) or B-1b B cells [17,18], thymus-dependent antibody responses to protein antigens are largely normal [9][10][11][12]. The loss of such a negative regulator would be anticipated to lead to stronger B cell responses.…”

CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity

“…One possibility is that they are more sensitive to dysregulated signaling in the absence of CD22 ( 34 ); but it is also noteworthy that MZ precursors express the highest levels of CD22 of any B cell subset ( 35 ), implying that CD22 may be more or less required during stages in B cell development. Mice expressing all of CD22 except the extracellular domains 1 and 2 (CD22Δ1-2 mice) have reduced MZ B cells but normal TI-2 Ab responses ( 15 , 36 , 37 ), so a MZ B cell deficiency alone is not sufficient to lead to impaired TI-2 Ab responses. Recently, Haas et al ( 36 ) reported that B-1b cells from CD22 −/− mice have impaired proliferative responses and elevated Ca 2+ responses to anti-IgM ligation and that CD22 −/− mice have reduced expansion of splenic B-1b B cells after immunization with TNP-Ficoll.…”

“…Mice expressing all of CD22 except the extracellular domains 1 and 2 (CD22Δ1-2 mice) have reduced MZ B cells but normal TI-2 Ab responses ( 15 , 36 , 37 ), so a MZ B cell deficiency alone is not sufficient to lead to impaired TI-2 Ab responses. Recently, Haas et al ( 36 ) reported that B-1b cells from CD22 −/− mice have impaired proliferative responses and elevated Ca 2+ responses to anti-IgM ligation and that CD22 −/− mice have reduced expansion of splenic B-1b B cells after immunization with TNP-Ficoll. There results suggest that whether or not CD22 −/− mice have defective TI-2 Ab responses depends on the Ag complexity and route of administration used.…”

“…Hass et al found CD22 −/− mice have elevated IgM and IgG Ab primary and secondary responses to DNP-KLH, while Jellusova et al found that CD22 −/− mice have reduced primary Ab responses to NP-OVA in alum ( 36 , 38 ). How can these differences be explained?…”

Duality of B Cell-CXCL13 Axis in Tumor Immunology

“…Also, B1 B cells can stimulate T cell expansion via CD80/CD86 and promote differentiation of CD4+ T cells (3). Similar to MZ B2 B cells, B1 B cells are capable of eliciting a T cell-independent response (40). B1 B cells differ from B2 B cells, in that they are larger, have resistance to FAS-induced apoptosis, and possess greater ex vivo survivability (41).…”