TLR-Induced Murine Dendritic Cell (DC) Activation Requires DC-Intrinsic Complement

Abstract

Induction of pro-inflammatory T cell immunity is augmented by innate dendritic cell (DC) maturation commonly initiated by Toll-like receptor (TLR) signaling. We demonstrate that ligation of TLR3, 4, and 9 induces murine DC production of complement components and local production of the anaphylatoxin C5a. In vitro, ex vivo, and in vivo analyses show that TLR-induced DC maturation as assessed by surface phenotype, expression profiling by gene array, and functional ability to stimulate T cell responses, requires autocrine C3a- and C5a-receptor (C3ar1/C5ar1) signaling. Studies employing bone marrow chimeric animals and Foxp3-GFP/ERT2-Cre/dTomato fate mapping mice show that TLR-initiated, DC autocrine C3ar1/C5ar1 signaling causes expansion of effector T cells and instability of regulatory T cells and contributes T cell-dependent transplant rejection. Together, our data position immune cell-derived complement production and autocrine/paracrine C3ar1/C5ar1 signaling as crucial intermediary processes that link TLR-stimulation to DC maturation and the subsequent development of effector T cell responses.

C5aR1 regulates migration of suppressive myeloid cells required for costimulatory blockade-induced murine allograft survival

“…While we showed here that C5aR1 ligation directly stimulates Mreg chemotaxis to the allograft (resulting in immunoregulation), C5a/C5aR1 signaling directly on T cells activates phosphatidylinositol‐4,5‐bisphosphate 3‐kinase γ–dependent AKT phosphorylation, which stimulates T cell proliferation and inhibits apoptosis, and simultaneously prevents Foxo1‐dependent Foxp3 production to limit Treg induction and function . C5a/C5aR1 interactions activate DCs, manifested by increased expression of costimulatory molecule and innate cytokine production, which also contribute to Teff differentiation and expansion while inhibiting Tregs . Differential effects of complement/C5aR1 signaling on various cell types likely explain why the absence of complement components prevents graft tolerance under some experimental conditions, yet promotes tolerance to alloantigens in other circumstances .…”

“…The complement system has been traditionally considered a component of innate immunity. Our cumulative work since 2005 has delineated unanticipated roles for complement, including autocrine C5a/C5aR1 ligations in T cells and dendritic cells (DCs), as crucial signals that activate CD4 + Teffs and inhibit the generation, function, and stability of Tregs, together augmenting T cell immunity . The absence/blockade of these signals inhibits CD4 + Teffs and enhances the generation, function, and stability of Tregs, favoring immune tolerance.…”

The complex functioning of the complement system in xenotransplantation

“…When co‐cultured with DCs, C4 was found to increase the regulatory T‐cell count . Expansion of T‐cell numbers and destabilization of regulatory T cells results in T cell–dependent transplant rejection …”

“…40 C1q, iC3b, C5a-C5aR, CR1, and factor H are reported to regulate the maturation and function of DCs. 24,25,[55][56][57] CR2 is part of the co-receptor (along with CD19, CD81, and Leu13) of B lymphocytes. 58,59 In the germinal centers, C3 degradation fragment-coated immune complexes are recognized and retained by follicular DCs, enhancing the differentiation of memory and effector B cells.…”

C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans

“…The complement system, conventionally connected with innate immunity, is known to function as an effector arm of antibody-initiated immune injury (27)(28)(29). Complement also regulates B cell activation thresholds (30) and crucially regulates proinflammatory T cell immune responses (31)(32)(33)(34), including those to alloantigens (32,(35)(36)(37)(38)(39). Despite these established associations, whether the complement system is mechanistically linked to Tfh cell induction and/or function and to the pathogenesis of Tfh cell-dependent diseases, including some models of chronic GvHD, remains incompletely understood.…”