CD19 is critically involved in establishing intrinsic B cell signaling thresholds through modulating both B cell receptor (BCR)-dependent and independent signaling [16, 17]. It plays roles in the antigen-independent development as well as the immunoglobulin-induced activation of B cells. CD19 is thus critical for the body to mount an optimal immune response. CD19 works in complex with the BCR and other surface molecules to allow both direct and indirect recruitment and binding of various down-stream protein kinases [6, 18]. The protein kinases that interact with the CD19 complex include those belonging to the Src family (Lyn, Fyn), Ras family, Abl, Btk, adapter molecules (Vav, Grb2), and PI3K . More recently, it has been recognized that CD19 is required for optimal MHC class II-mediated signaling, through its modulation of tyrosine phosphorylation and Akt kinase signaling .
CD19 functions as the dominant signaling component of a multimolecular complex on the surface of mature B cells, alongside complement receptor CD21 (CD2), and the tetraspanin membrane protein CD81 (TAPA-1), as well as CD225 [9, 13, 18, 20] (Figure 2). The CD19 complex functions to decrease the threshold for receptor-dependent signaling through modulating both intrinsic and receptor-induced signals [11, 12, 18]. CD19 acts as a critical co-receptor for BCR signal transduction [13, 21]. As BCR signaling requires protein tyrosine kinase (PTK) activation, CD19 recruits and amplifies the activation of Src-family protein tyrosine kinases such as Lyn and Fyn [9, 13, 22]. Upon BCR activation, CD19 also enhances BCR-induced signaling crucial for B cell expansion, through recruitment and activation of PI3K and downstream Akt kinases .
The CD19/CD21 complex is also capable of, independent of the BCR, reacting and binding to activated complement fragment C3d. This complex subsequently translocates into membrane “lipid rafts” domains, where tyrosine phosphorylated CD19 can then interact with co-localized kinases in the membrane to modulate BCR signaling . Normally, more CD19 is found associated with CD21 than in complex with BCR, and a dramatic increase in B-cell activation results from the simultaneous binding of surface antigen by B-cell Ig and of C3d by CD21. Studies also showed that CD19 does not require CD21 for signal transduction, and CD19/21 complex signaling is induced by the binding of C3d to CD21 [13, 14].
CD81 functions as a part of the tetraspanin web as well as a chaperone protein. It provides docking sites for molecules involved in various signal transduction pathways, and is important for the expression of CD19. CD19 expression in B cells of CD81−/− mice were found to be ~30–50% of that in wild type (WT) mice, while expression of CD21 and the BCR were at their respective WT levels [25, 26]. CD19/CD38 have been shown to co-localize in lipid rafts and physically interact with another surface antigen receptor, CD38, in mice B cell. The two receptors have been shown to be a part of the B cell signaling complex [24, 25]. In vivo, CD81-deficient mice show reduced CD19 expression and overall B cell signaling. In the absence of CD81 expression, CD19 expression is halved .
CD19 is thought to play duel roles in B cell activation. First, it functions as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane. Experiments have shown that CD19 tyrosine residues are phosphorylated. The tyrosine phosphorylated CD19 can recruit SH2 domain–containing cytosolic proteins after ligation with the BCR. The second role of CD19 is as a signal subunit for the CD19/CD21 complex when colligated with the BCR, where Ag bearing complement enhances B-cell activation via BCR-CD19/CD21 coligation [4, 12, 21, 27].
In addition, CD19 is involved with, though not essential, in the regulation of bone marrow development through its actions on bone marrow cells via altering BCR signals . Others have proposed a critical role for CD19 in the process of B cell development from their early differentiation events in the bone marrow to late maturation steps in the spleen . In developing B cells, CD19 is capable of modulating signal thresholds independent of the BCR. In fact, CD19 signaling may play a role in controlling the progression of early pre-B to small, resting pre-B cells in the bone marrow by associating with components of the pre-BCR.