| Abstract: | CD31 is a transhomophilic tyrosine-based inhibitory motif receptor and is expressed by both dendritic cells (DCs) and T lymphocytes. Previous studies have established that the engagement of CD31 drives immune-inhibitory signaling in T lymphocytes, but the effect exerted by CD31 signaling in DCs remains elusive. Here, we show that CD31 is a key coinhibitory receptor on stimulated DCs, favoring the development of tolerogenic functions and finally resulting in T-cell tolerance. The disruption of CD31 signaling favored the immunogenic maturation and migration of resident DCs to the draining lymph nodes. In contrast, sustaining the CD31/SHP-1 signaling during DC maturation resulted in reduced NF-κB nuclear translocation, expression of costimulatory molecules, and production of immunogenic cytokines (e.g., IL-12, IL-6), whereas the expression of TGF-β and IL-10 were increased. More importantly, CD31-conditioned DCs purified from the draining lymph nodes of ovalbumin-immunized mice favored the generation of antigen-specific regulatory T cells (CD25+ forkhead box P3+) at the expense of effector (IFN-γ+) cells upon coculture with naive ovalbumin-specific CD4+ T lymphocytes ex vivo. Finally, the adoptive transfer of CD31-conditioned myelin oligodendrocyte glycoprotein-loaded DCs carried immune tolerance against the subsequent development of MOG-induced experimental autoimmune encephalomyelitis in vivo. The key coinhibitory role exerted by CD31 on DCs highlighted by the present study may have important implications both in settings where the immunogenic function of DCs is desirable, such as infection and cancer, and in settings where tolerance-driving DCs are preferred, such as autoimmune diseases and transplantation.Dendritic cells (DCs) have an essential function in initiating CD4+ T-cell responses by recognizing and presenting specific antigens associated with danger signals (1, 2). These signals contribute to conferring a fully mature, immunogenic phenotype to DCs, which is characterized by the up-regulation of MHC costimulatory molecules (e.g., CD40, CD86, CD80). The ensuing up-regulation of the chemokine (C-C motif) receptor type 7 (CCR7) receptor enables the migration of DCs to draining lymph nodes following the chemokine (C-C) motif ligand 21 (CCL21) gradient (3, 4). Finally, the fully matured DCs produce the proinflammatory cytokines IL-1β, TNF, IL-12, and IL-6 (5). Importantly, DCs can also exert the opposite function by tolerizing T cells against self-antigen–directed immune responses, which is necessary to minimize autoimmune reactions. However, insufficient DC immunogenicity and excessive tolerance would favor the development of chronic infections and tumors. The immunogenic function of DCs depends on the balance between activating and inhibitory signals that occur at the time of DC maturation (2).Elucidating the inhibitory receptors that are involved in the control of DC maturation would facilitate new interventional strategies to control autoimmune diseases. Despite intensive work in this area (6), the coinhibitory receptors involved in the control of DC immunogenic functions remain poorly understood. Ig-like immunoreceptor tyrosine-based inhibitory motif (ITIM) receptors are thought to play an essential role in inhibiting the maturation of DCs (7).Among the Ig-like ITIM receptors, we propose that CD31 (8, 9) (also known as PECAM-1) may play an important role in DC function because CD31 is constitutively expressed on these cells (10). Moreover, CD31 is essentially engaged by homophilic binding (11), which remarkably occurs between interacting cells of the innate and adaptive immune system.The low-affinity, transhomophilic engagement of CD31 (11) triggers downstream inhibitory signaling (9), leads to the detachment of CD31+ lymphocytes from the cells of the innate immune system (12), and raises the activation threshold of lymphocytes via the phosphorylation of CD31 ITIMs and the recruitment of SH2 domain-containing tyrosine phosphatase (e.g., SHP-1, SHP-2) upon the engagement of the antigen receptor (13–16). Nevertheless, the role played by CD31 in maturing DCs remains to be elucidated.Interestingly, it has been shown that during LPS-driven maturation, CD31 expression is consistently reduced on human monocyte-derived DCs (17–19) and endotoxin-induced septic shock is exaggerated in CD31−/− mice (20, 21). In addition, autoimmune disease models dependent on antigen presentation are accelerated in the absence of CD31 (22, 23), suggesting that the effective presentation of the immunizing antigens involved in specific adaptive immune responses is favored by the absence of CD31.Here, we demonstrate that the disruption of CD31 signaling favors the maturation and subsequent migration of antigen-loaded DCs to the draining lymphoid organs, driving more rapid and effective antigen-specific T-cell responses. In contrast, upholding the CD31/SH2 domain-containing tyrosine phosphatase-signaling pathway with an agonist peptide reduces the extent of maturation of the DCs, which become tolerogenic toward recall antigens both in vitro and in vivo. |
