CD19 Can Regulate B Lymphocyte Signal Transduction Independent of Complement Activation

Abstract

B lymphocytes are critically regulated by signals transduced through the CD19-CD21 cell surface receptor complex, where complement C3d binding to CD21 supplies an already characterized ligand. To determine the extent that CD19 function is controlled by complement activation, CD19-deficient mice (that 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 loss of CD21 and C3 expression, respectively. Mature B cells from CD21-deficient littermates had ∼36% higher cell surface CD19 expression, whereas CD21/35 expression was increased by ∼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. Otherwise, B cell development and function in CD19-deficient and -overexpressing mice were not significantly affected by a simultaneous loss of CD21 expression. Although CD21-deficient mice were found to express a hypomorphic cell surface CD21 protein at low levels that associated with mouse CD19, C3 deficiency 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.

Defective B cell ontogeny and immune response in human complement receptor 2 (CR2, CD21) transgenic mice is partially recovered in the absence of C3

“…Furthermore, despite peripheral B cells in the C3 −/− hCR2 high mice having equivalent surface IgM levels they displayed a 3 fold increase in hCR2, a 1.5 fold increase in mCR1/2 and a significant increase in CD19 expression levels when compared to B cells isolated from mice which expressed normal levels of C3 ( Figure 5B-F). In the case of mCR1/2 and CD19, these data are in complete agreement with those previously reported on the C3 −/− background (Hasegawa et al, 2001). Thus, the increase in hCR2 expression levels in C3 −/− background suggests that it has been integrated into the mechanisms that modulate the expression levels of endogenous co-receptor proteins on the B cell surface.…”

“…The fact that addition of C3 containing sera can result in rapid down regulation of members of the CR2/ CD19 signaling complex suggests that tight regulation or feedback on expression levels of these molecules exist. This data fits with the idea that a common regulatory loop exists between C3, CR1/2 and CD19 that influences B cell signaling thresholds as suggested by Tedder and colleagues (Hasegawa et al, 2001). Our bone marrow data demonstrates the regulation of hCR2 expression levels in the presence of C3 is at the transition between B220 lo and B220 hi status and thus, is likely to be concurrent with the expression of sIgM or pre-BCR.…”

“…The removal of C3 resulted in an almost 3 fold increase in B cell surface expression level of hCR2 compared to hCR2 expression levels in the presence of C3 ( Figure 4A). A significant increase in B cell surface expression of mouse CR1/2 and CD19 on the C3 −/− background was also noted ( Figure 4B and C) and has been previously reported by Hasegawa et al (Hasegawa et al, 2001). This data demonstrates that despite hCR2 being expressed by an exogenous promoter (a mouse Vλ2 promoter-Vλ2-4 enhancer minigene (Marchbank et al, 2002)), hCR2 is being treated or responded to in a manner very similar to that of the endogenous murine members of the CR2/CD19 signaling complex.…”

“…In the case of hCR2 tg mice, the point of hCR2 expression also appears to be associated with the 'negative effects' on B cells which is greater after removal of CD19. However, the analysis of CR1/2 −/− CD19 −/− did not find any recovery in B cell numbers at this point when compared to CD19 −/− mice and suggests that mCR1/2 is not directly involved in the loss of B cells (Hasegawa et al, 2001). It is worth noting that the CR1/2 mice used in that study expressed a hypomorphic mCR1/2 that still associates with CD19 and after binding with C3d could allow this molecule to be involved in signaling.…”

Polymorphisms of human CD19 gene: possible association with susceptibility to systemic lupus erythematosus in Japanese

“…It was also reported that IgM and heparan sulfate binds to CD19 as complement-independent ligands. 8,9 CD19 has also been implicated as a signaling partner for several other surface receptors including CD40, 10 CD38, 11 CD72, 10 VLA4 12 and Fc␥RIIB. 13,14 Altering CD19 density on the cell surface in gene-targeted or transgenic mice has been shown to significantly influence B cell functions.…”