BCR-dependent lineage plasticity in mature B cells

Abstract

B2 cells engage in classical antibody responses, whereas B1 cells are considered carriers of innate immunity, biased toward recognizing epitopes present on the surfaces of common pathogens and self antigens. To explore the role of B cell antigen receptor (BCR) specificity in driving B1 cell differentiation, we developed a transgenic system allowing us to change BCR specificity in B cells in an inducible and programmed manner. Mature B2 cells differentiated into bona fide B1 cells upon acquisition of a B1 cell–typical self-reactive BCR through a phase of proliferative expansion. Thus, B2 cells have B1 cell differentiation potential in addition to their classical capacity to differentiate into memory and plasma cells, and B1 differentiation can be instructed by BCR-mediated self-reactivity, in the absence of B1-lineage precommitment.

Self‐reactivity on a spectrum: A sliding scale of peripheral B cell tolerance

“…28,31 Indeed, work from the Barton laboratory shows that expansion of PtC-specific BCRs in the B1a compartment is regulated by endosomal TLRs that recognize nucleic acids. For example, the profound restriction of the B1a repertoire and unique capacity of PtC-specific BCR Tgs to drive B1a fate suggests that antigen recognized by such BCRs delivers additional signals superimposed on "strong" BCR stimulation.…”

“…[28][29][30] Forced expression of such BCRs via Tg models greatly expands the pool of B1a cells, and recent provocative work from Rajewsky and colleagues suggests this BCR specificity may even be sufficient to "convert" B2 cells into "B1a-like" cells. 29,31 Hayakawa and colleagues showed formally that Thy-1 antigen expression is necessary for Thy-1-specific (anti-Thy-1 Ab or ATA) B cells to enter the B1a compartment. 32,33 By contrast, marginal zone (MZ) ATA B cell development is disfavored both at high levels of antigen and in the complete absence of antigen, but proceeds optimally at low levels of antigen, providing striking evidence not only for a sharp upper threshold for negative selection, but also a minimal degree of self-reactivity required for positive selection into this compartment.…”

“…For example, the profound restriction of the B1a repertoire and unique capacity of PtC-specific BCR Tgs to drive B1a fate suggests that antigen recognized by such BCRs delivers additional signals superimposed on "strong" BCR stimulation. 28,31 Indeed, work from the Barton laboratory shows that expansion of PtC-specific BCRs in the B1a compartment is regulated by endosomal TLRs that recognize nucleic acids. 44 Conversely, endosomal…”

Secreted IgM: New tricks for an old molecule

“…With regard to the specificity of IgM, current evidence suggests that the pool of natural IgM‐secreting B‐1 cells is positively selected upon the recognition of self‐antigens during development . This explains the highly skewed, self‐reactive repertoire of natural IgM and the fact that the antigen‐specificity of B‐1 cells is tightly linked to their unique functions . Given the similarity in the B‐1a cell repertoire of gnotobiotic and conventional‐housed mice, it then appears that self‐antigen recognition shapes the B‐1 cell repertoire through activation and clonal expansion, which explains the strong changes in VH‐usage over the first few months of life .…”

“…66 This explains the highly skewed, self-reactive repertoire of natural IgM and the fact that the antigen-specificity of B-1 cells is tightly linked to their unique functions. 67 Given the similarity in the B-1a cell repertoire of gnotobiotic and conventional-housed mice, it then appears that selfantigen recognition shapes the B-1 cell repertoire through activation and clonal expansion, which explains the strong changes in VH-usage over the first few months of life. 58,65 How B-1 cells can be selected and then differentially activated by self-antigens to secrete self-reactive IgM, without this process resulting in autoimmune disease development is a further important but unresolved question.…”