CD19 can regulate B lymphocyte signal transduction independent of complement activation

B lymphocytes are critically regulated by signals transduced through the CD 19-CD21 cell surface receptor complex, where complement C3d binding to CD21 supplies an already characterized ligand. To determine the extent that CD1 9 function is controlled by complement activation, CD19-deficient mice (tha t are hyporesponsive to transmembrane signals) and mice overexpressing CD19 (that are hyperresponsive) were crossed with CD21- and C3-deficient mice. Cell surface CD19 and CD21 expression were significantly affected by the lo ss of CD21 and C3 expression, respectively. Mature B cells from CD21-defici ent littermates had similar to 36% higher cell surface CD19 expression, whe reas CD21/35 expression was increased by similar to 45% on B cells from C3- deficient mice. Negative regulation of CD19 and CD21 expression by CD21 and C3, respectively, may be functionally significant because small increases in cell surface CD19 overexpression can predispose to autoimmunity. Otherwi se, B cell development and function in CD19-deficient and -overexpressing m ice were not significantly affected by a simultaneous loss of CD21 expressi on. Although CD21-deficient mice were found to express a hypomorphic cell s urface CD21 protein at low levels that associated with mouse CD19, C3 defic iency did not significantly affect B cell development and function in CD19- deficient or -overexpressing mice. These results, and the severe phenotype exhibited by CD19-deficient mice compared with CD21- or C3-deficient mice, collectively demonstrate that CD19 can regulate B cell signaling thresholds independent of CD21 engagement and complement activation.