The CD19/CR2/TAPA-1 complex of B lymphocytes: linking natural to acquired immunity
1Wellcome Trust Immunology Unit, University of Cambridge School of Clinical Medicine, United Kingdom.
Insights
CD19 enhances B cell sensitivity to antigens by associating with the B cell receptor. This complex lowers the threshold for B cell activation, improving the immune response to low antigen concentrations.
Area of Science:
- Immunology
- Cell Biology
Background:
- B cells require high sensitivity to detect low antigen concentrations during primary immune responses.
- B cell antigen receptors often have low affinity, posing a challenge for effective antigen recognition.
Purpose of the Study:
- To investigate the role of CD19 in enhancing B cell sensitivity to antigen.
- To elucidate the molecular mechanisms by which CD19 modulates B cell receptor signaling.
Main Methods:
- Investigated CD19's association with the B cell receptor complex.
- Examined the signaling pathways downstream of CD19 cross-linking, including phospholipase C and PI3' kinase.
- Studied the interactions of CD19 with other membrane proteins like CR2 (CD21) and TAPA-1.
Main Results:
- Cross-linking CD19 with membrane immunoglobulin (mIg) significantly reduces the number of mIg needed for B cell activation (e.g., phospholipase C activation, DNA synthesis).
- CD19 signaling is mediated by protein tyrosine kinases (PTKs), including lyn, and links to PLC and PI3' kinase.
- CD19 forms a complex with CR2 and TAPA-1, facilitating antigen recognition through complement fragments and promoting cell-cell interactions.
Conclusions:
- CD19 plays a crucial role in amplifying B cell receptor signaling, enabling B cells to respond to low antigen levels.
- The CD19-CR2-TAPA-1 complex integrates signals from various pathways, enhancing B cell activation and interaction.
- CD19 is essential for balancing broad antigen specificity with high sensitivity in B cells.
Abstract:
B lymphocytes must respond to low concentrations of antigen despite having low affinity antigen receptors during the primary immune response. CD19, a B cell-restricted membrane protein of the immunoglobulin superfamily that associates with the antigen receptor complex, may help the B cell meet this requirement. Cross-linking CD19 to membrane immunoglobulin (mIg) lowers, by two orders of magnitude, the number of mIg that must be ligated to activate phospholipase C (PLC) or to induce DNA synthesis. CD19 is coupled, via protein tyrosine kinases (PTKs), to PLC and phosphatidylinositol 3' kinase (PI3' kinase), and it interacts with the Src-type nonreceptor PTK lyn. It also associates with two other membrane proteins, CR2 (complement receptor type 2, CD21), which permits nonimmunologic ligation of CD19, and TAPA-1, a member of the tetraspan family of membrane proteins. CR2 binds fragments of C3 that are covalently attached to glycoconjugates. This indirectly enables CD19 to be cross-linked to mIg after preimmune recognition of an immunogen by the complement system. CR2 also can be ligated by CD23, a lectin-like membrane protein that resides on cells that may present antigen to B cells. TAPA-1 associates with several other membrane proteins on B and T cells, including MHC class II, CD4, and CD8, and it promotes Ca2(+)- and LFA-1-independent homotypic aggregation when ligated directly or indirectly through CD19 or CR2. This may facilitate interaction of the B cell with other cells essential for cellular activation. The formation of this membrane protein complex by representatives of three different protein families helps the B cell resolve its dilemma of combining broad specificity with high sensitivity.
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