CD22 IS A NEGATIVE REGULATOR OF B-CELL RECEPTOR SIGNALING

Background: Antibody responses are triggered by binding of antigen to the B-cell antigen receptor (BCR). The strength of the resulting signa l determines the outcome of the response, which may vary from the indu ction of tolerance to the antigen, to the production of specific high- affinity antibodies. Additional cell-surface proteins assist the BCR i n its function, and can facilitate or inhibit an antibody response. CD 22 is a BCR-associated transmembrane protein, the cytoplasmic tail of which contains three immunoreceptor tyrosine-based inhibitory motifs. These motifs are phosphorylated upon BCR-crosslinking, and can bind th e tyrosine phosphatase SHP-1, a putative negative regulator of signall ing from the BCR. In order to assess the role of CD22 in vivo, we have generated CD22(-/-) mice by targeted gene inactivation. Results: In C D22(-/-) mice, B-cell development is normal. There are normal numbers of peripheral B cells, but these have a more mature phenotype. In addi tion, recirculating B cells are absent from the bone marrow. However, the distribution of the two B-cell subtypes, B-1 and B-2, is normal. A fter BCR-crosslinking in vitro, splenic CD22(-/-) B cells show an incr eased Ca2+ influx and a lower survival due to an increased induction o f apoptosis. In contrast, there is an increased proliferative response to the B-cell mitogen lipopolysaccharide (LPS). A shorter average lif espan in the B-cell compartment is also found in vivo. Furthermore, T- cell independent immune responses are impaired, whereas T-cell depende nt responses are normal. Conclusions: The absence of CD22 expression l owers the signalling threshold for BCR-crosslinking and can thus influ ence the fate of the B cell. We propose that the low threshold leads t o hyperresponsiveness of the B cells and a chronic basal activation. I n this model, engagement of the receptor without T-cell help leads to an increased induction of apoptosis, thus explaining the shorter lifes pan of CD22(-/-) B cells and the low response to T-cell independent an tigens. The alteration in B-cell phenotype and the higher levels of LP S-reactivity are attributable to the chronic basal stimulation.