Figure 1. B-cell receptor signaling during B-cell development and for B-cell differentiation after the encounter with the antigen.

(1) Common lymphoid progenitor (CLP) cells commit to the B-cell lineage when they start expressing the B220 isoform of CD45. (2) Pro-B cells undergo DJ rearrangements and become pre-B cells when they express membrane forms of μ heavy chains with surrogate light chains (pink dotted lines) in the pre-B receptor. The transition between pro-B and pre-B cells has been described as being dependent on membrane association of Igα/Igβ complexes and their ability to generate basal signals. It seems that pre-B receptors do not have a ligand-recognition function ^{40, 41}. (3) After VDJ recombination in the pre-B cell stage, immature B cells pair light chains with μ chains to form monomeric IgM, which is expressed at the cell surface in association with Igα/Igβ to form the B-cell receptor (BCR). Newly formed immature B cells exit the bone marrow to reach the spleen, where, as transitional B cells, they will complete their maturation before entering the follicles or the marginal zone (MZ). (4) BCR signaling strength appears to have a critical role during follicular (Fo) or MZ B-cell differentiation. There is evidence of at least two possibilities ^{29, 30, 36, 42– 44}: increased BCR signaling could drive differentiation to Fo B cells or to MZ B cells. This could depend on other factors such as the microenvironment or the timing of BCR signaling. (5) Mature naïve B cells are ready to respond to antigens. By specifically binding antigen through the BCR, B cells are activated and differentiate into plasma cells through extra-follicular differentiation (6) or start the T-cell-dependent germinal center (GC) reaction (7). The mechanism of activated B cells entering the GC reaction or undergoing rapid plasma cell differentiation in extra-follicular proliferative foci is controlled by the nature of the interaction between the BCR and antigen. Responding clones that undergo a strong initial interaction with antigen can efficiently differentiate into extra-follicular plasma cells ⁴⁵. However, it has also been shown that B cells expressing higher-affinity BCRs are more competitive to become pre-GC B cells during T–B interaction ^{46, 47}. This seems contradictory, but timing may be a very important factor. B cells in the GC reaction are selected on the basis of their interaction with the antigen through BCRs. Based on how efficiently B cells present antigen to Fo T helper cells, they are allowed to further differentiate inside the GC. Whether this BCR–antigen interaction results in significant signaling and has a role for selection is not clear.