Figure 2.

Local complement activation: the fundamental role of “complosome”. (A) T-cell-expressed protease cathepsin L (CTSL) processes C3 into biologically active C3a and C3b. “Tonic” intracellular C3a generation is required for homeostatic T cell survival through mTOR activation. This intracellular CS is defined as “complosome”. (B) As a result of T cell activation, the activated intracellular complement and complement receptors are secreted by T cells; C3a and C3b bind to C3aR and CD46 (membrane cofactor protein, MCP), respectively, and promote protective T Helper1 (Th1) differentiation. The activation of T cell receptors (TCRs) promotes also intracellular C3, C5, FH, FD secretion. Moreover, intracellular C5 activation (induced by CD46) and stimulation of C5a receptor 1 (C5aR1) promote pyrin-domain-containing protein 3 (NLRP3) inflammasome assembly, caspase-1-dependent interleukin-1β secretion, and induction of Th1 functional activation. In the early stages, CD46 promotes differentiation and expansion of T cells into Th1 effector lymphocytes. However, in the second phase, CD46, in association with the IL-2 receptor (IL-2R), leads to a Th1 restriction, promoting the secretion of IL-10. This is associated with the expression of C5aR2 via surface-shuttled C5a/C5a-desArg, which probably has a role in assisting this inhibitory signal. In addition, a synergistic effect has been observed between Toll-like receptor (TLR) and complement receptors expressed on the antigen-presenting cells (APCs). Abbreviations. APC, antigen-presenting cells; CTSL, T-cell-expressed protease cathepsin L; MHC II, major histocompatibility complex class II; TLR, Toll-like receptor; C3aR, C3a receptor; C5aR, C5a receptor; IL-2R, interleukin-2 receptor; NLRP3, NLR family pyrin-domain-containing 3.