Complement regulation of T-cell alloimmunity

Abstract

Complement proteins are generated both by the liver (systemic compartment) and by peripheral tissue-resident cells and migratory immune cells (local compartment). The immune cell-derived, alternative pathway complement components activate spontaneously, yielding local, but not systemic, production of C3a and C5a. These anaphylatoxins bind to their respective G-protein-coupled receptors, the C3a receptor and the C5a receptor, expressed on T cells and antigen-presenting cells, leading to their reciprocal activation and driving T-cell differentiation, expansion, and survival. Complement deficiency or blockade attenuates T-cell-mediated autoimmunity and delays allograft rejection in mice. Increasing complement activation, achieved by genetic removal of the complement regulatory protein decay accelerating factor, enhances murine T-cell immunity and accelerates allograft rejection. Signaling through the C3a receptor and the C5a receptor reduces suppressive activity of natural regulatory T cells and the generation and stability of induced regulatory T cells. The concepts, initially generated in mice, recently were confirmed in human immune cells, supporting the need for testing of complement targeting therapies in organ transplants patients.

Keywords: Allograft rejection; T cells; complement; costimulation; transplantation.

Figure 1

Schematic representation of complement activation pathways. (A) Three pathways lead to complement activation: classical, mannose-binding lectin (MBL), and alternative. Binding of immune complexes to C1q,r,s activates the classical pathway whereas binding of mannose-associated serine protease (MASPs) to mannose motifs expressed on bacteria activate the MBL pathway. Subsequent cleavage and assembly of C2 and C4 proteins form the C3 convertase. The spontaneous hydrolysis of C3 on cell surfaces leads to an alternative pathway: C3 convertase dependent on factor B (fB), factor D (fD), and properdin. C3 convertases cleave C3 into C3a and C3b. C3b permits the formation of C5 convertase. C3b has further roles in opsonization and immune complex clearance. C3a and C5a have inflammatory and chemotactic properties. C5b, in conjunction with C6-C9, allows formation of the membrane attack complex and subsequent pathogen lysis. (B) DAF (CD55), is a cell surface–expressed complement regulator that accelerates the decay of all surface-assembled C3 convertases, thereby limiting amplification of the downstream cascade. Reprinted with permission from Kwan et al.

Figure 2

Schematic representation of complement-mediated effects on T cells and APCs. C3aR/C5aR signaling on both APC and T cells activates the AKT pathway by phosphorylation (among other pathways). AKT activation on the APC stimulates maturation, cytokine production, and B7 costimulatory molecule expression. AKT activation on the T cell directly promotes IFN-γ secretion, reduces susceptibility to apoptosis, and promotes cell proliferation and reduces iTreg generation and stability. In this manner, C3aR/C5aR stimulation directly and indirectly promotes T-cell maturation with an expanded effector repertoire. Modified with permission from Kwan et al.

Figure 3

C3aR and C5aR on T cells regulate GvHD in mice. Weight change of BALB/c recipients of B6 bone marrow plus WT or C3ar1^−/−C5ar1^−/− T cells (1.5 × 10⁵ per mouse). *P < .05 versus WT. Reprinted with permission from Kwan et al.

Figure 4

Recipient Daf1 deficiency results in cardiac allograft rejection despite CD4 depletion. Survival of BALB/c hearts transplanted into B6 WT (n = 12), Daf1^−/− (n = 5), CD4-depleted WT (n = 5), and CD4-depleted Daf1^−/− (n = 6). *P < .05 versus CD4-depleted Daf1^−/−, **P < .05 versus WT controls. Reprinted with permission from Vieyra et al.

Figure 5

C3aR−/− nTreg cells more efficiently prevent autoimmune colitis and skin allograft rejection in vivo. (A) Weights of animals given CD45.1 Tconv cells alone (closed circles, n = 3), T conv cells plus 2:1 CD45.2+ WT nTreg cells (open squares, n = 10), or Tconv cells plus 2:1 C3ar1^−/−C5ar1^−/− nTreg cells (open triangles, n = 10). Data are pooled from two individual experiments. (B) BALB/c tail skin graft survival in B6 rag1^−/− recipients receiving Tconv cells alone (black, n = 3), Tconv cells + WT nTreg (blue, n = 12), or T conv cells + C3ar1^−/−C5ar1^−/− nTreg (red, n = 12). *P < .05 versus no nTreg cells; **P = .05 versus WT nTreg. Reprinted with permission from Kwan et al.