Complement and adaptive immunity. (A) B cells express complement receptor 2 (CR2; CD21), which binds to C3dg, a C3 breakdown product that functions as an opsonin. C3dg-coated antigens recognized by antigen-specific B-cell receptors plus CR2 initiate engulfment and lower the threshold of B-cell activation, promoting antibody production. (B) Cognate interactions between T cells and antigen-presenting cells (APCs) (T-cell receptor [TCR] +CD28/80/86 or CD40/154) upregulate the expression of multiple alternative pathway components, including C3, C5, fB, fD, C3aR, and C5aR, while simultaneously downregulating decay accelerating factor (DAF) expression (lifting restraint on complement activation). Locally produced C3a and C5a act in an autocrine/paracrine manner through AKT signaling to promote maturation and cytokine production of APCs, Th1/IFN-γ expression, increased proliferation, and decreased apoptosis of T cells. (C) Regulatory T-cell generation, stability, and suppressive function are decreased by C3a and C5a signaling-induced AKT signaling, which impairs nuclear translocation of Foxo1, a transcription factor for FoxP3. AKT, phosphokinase B; pAKT, phosphorylated phosphokinase B; BCR, B cell receptor; iTreg, murine-induced regulatory T cell.
