title: CD22 is a negative regulator of B-cell receptor signalling.
abstract: BACKGROUND
  . Antibody responses are triggered by binding of antigen to the B-cell antigen receptor (BCR). The strength of the resulting signal determines the outcome of the response, which may vary from the induction of tolerance to the antigen, to the production of specific high-affinity antibodies. Additional cell-surface proteins assist the BCR in its function, and can facilitate or inhibit an antibody response. CD22 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 the tyrosine phosphatase SHP-1, a putative negative regulator of signalling from the BCR. In order to assess the role of CD22 in vivo, we have generated CD22(-/-) mice by targeted gene inactivation.
  
  
  RESULTS
  . In CD22(-/-) mice, B-cell development is normal. There are normal numbers of peripheral B cells, but these have a more mature phenotype. In addition, 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. After BCR-crosslinking in vitro, splenic CD22(-/-) B cells show an increased Ca2+ influx and a lower survival due to an increased induction of apoptosis. In contrast, there is an increased proliferative response to the B-cell mitogen lipopolysaccharide (LPS). A shorter average lifespan in the B-cell compartment is also found in vivo. Furthermore, T-cell independent immune responses are impaired, whereas T-cell dependent responses are normal.
  
  
  CONCLUSIONS
  . The absence of CD22 expression lowers the signalling threshold for BCR-crosslinking and can thus influence the fate of the B cell. We propose that the low threshold leads to hyperresponsiveness of the B cells and a chronic basal activation. In this model, engagement of the receptor without T-cell help leads to an increased induction of apoptosis, thus explaining the shorter lifespan of CD22(-/-) B cells and the low response to T-cell independent antigens. The alteration in B-cell phenotype and the higher levels of LPS-reactivity are attributable to the chronic basal stimulation.
authors.affiliation: Max-Planck-Institut für Immunbiologie, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Nitschke
authors.forename: R
authors.initials: R
authors.lastname: Carsetti
authors.forename: B
authors.initials: B
authors.lastname: Ocker
authors.forename: G
authors.initials: G
authors.lastname: Köhler
authors.forename: M C
authors.initials: MC
authors.lastname: Lamers
mesh_terms: D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D015815:Cell Adhesion Molecules; D002470:Cell Survival; D002478:Cells, Cultured; D017931:DNA Primers; D005434:Flow Cytometry; D037102:Lectins; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D051918:Sialic Acid Binding Ig-like Lectin 2; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D037102:Lectins; D011947:Receptors, Antigen, B-Cell; D051918:Sialic Acid Binding Ig-like Lectin 2; D002118:Calcium