CD40/CD154 Interactions at the Interface of Tolerance and Immunity

Abstract

Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alpha CD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.

CD40L expressed from the canarypox vector, ALVAC, can boost immunogenicity of HIV-1 canarypox vaccine in mice and enhance the in vitro expansion of viral specific CD8+ T cell memory responses from HIV-1-infected and HIV-1-uninfected individuals

“…Recent advances in immunology have shown that several types of molecules may be used as novel adjuvants to enhance immunogenicity of vaccines, such as cytokines, chemokines, Toll-like receptor ligands, and some costimulatory molecules [44][45][46][47]. Among these molecules, CD40L is attractive since it is one of the main mechanisms by which CD4 + T cells provide help to CTL and B cells [16,18,19,31]. The CD4 + T-cell-replacement activity of CD40L in our DC co-culture experiments is especially intriguing in the setting of development of a therapeutic vaccine for HIV-1.…”

“…Several members of tumor necrosis factor/tumor necrosis factor receptor superfamily (TNFSF/TNFRSF), including CD40L (CD154)/CD40, have been shown to enhance immunity by promoting expansion and survival of T, B, and dendritic cells (DCs) [15][16][17]. CD40L-CD40 interaction is considered as the main pathway through which CD4 + T cells provide help for the generation of CD8 + T cell responses and T cell dependent antibody responses [16,18,19].…”

“…CD40L-CD40 interaction is considered as the main pathway through which CD4 + T cells provide help for the generation of CD8 + T cell responses and T cell dependent antibody responses [16,18,19]. CD40L is a type II membrane protein predominantly expressed on activated CD4 + T cells.…”

B7-DC/PD-L2 Cross-Linking Induces NF-κB-Dependent Protection of Dendritic Cells from Cell Death

“…Among the transcription factors activated by the TLR gene family, NF-B is a key regulator of the expression of molecules that mediate intercellular communication among leukocytes (9,10). TNF-␣ and CD40L can also activate the maturation process of DC, inducing signaling pathways mediated by TNFR or CD40 coupled TNFR-associated factor adaptors (11,12).…”

Potential role of CARMA1 in CD40‐induced splenic B cell proliferation and marginal zone B cell maturation

“…CD40 belongs to the super-family of TNF receptors, and expression of CD40 is detected during early B cell ontogeny [27][28][29][30]. In mature B cells, signaling through CD40 promotes survival, somatic hyper-mutation and class-switch recombination, and the defective CD40 signaling results in hyper-IgM syndrome [31,32].…”