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CD40/CD40L Signaling Pathway


Figure 1. CD40/CD40L signaling pathway.

Introduction

Cluster of differentiation 40, CD40 (also known TNFRSF5, Tumor necrosis factor receptor superfamily member 5.) is a costimulatory protein and expresses on antigen presenting cells (APC). In human, CD40 is coded by TNFRSF5 gene and has 7 transcripts. Its ligand, CD154 (CD40L), is a protein that is primarily expressed on activated T cells and is also a member of the TNF superfamily of molecules. From previous studies, we can know that the CD40-CD40L pathway has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. The TNFR-receptor associated factor adaptor proteins TRAF1, TRAF2, TRAF6 and possibly TRAF5 interacting with CD40 serve as mediators of the signal transduction. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of CD40 and its ligand, which may be important for homotypic cell interactions. Besides, the interaction of CD40 and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis.

The function of pathway

Targeting the CD40L and CD40 pathway is a powerful means of attenuating autoreactive and alloreactive immune responses. The previous results show that the CD40L and CD40 pathway contributes to an enhancement of cellular immune responses by virtue of an interaction between CD40L expressed on activated antigen-specific CD4+ T cells and CD40 expressed on dendritic cells (DC). CD40 signaling into dendritic cells thereby transmits a signal to activate the APC, which results in upregulation of CD80, CD86, and other co-stimulatory molecules for the optimal stimulation of CD8+ antigen-specific T cell responses. In addition, CD40 also expresses in the macrophage and B cells. In macrophage, the primary signal for activation is IFN-γ from Th1 type CD4+T cells. The secondary signal is CD40L on the T cell which binds CD40 on the macrophage cell surface. As a result, the macrophage expresses more CD40 and TNF receptors on its surface which helps increase the level of activation. Increased activity results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species and nitric oxide, leading to the destruction of ingested microbe. B cells can also present antigens to helper T cells. If activated T cells recognize the peptide presented by the B cell, the CD40L on the T cell binds to the B cell's CD40 receptor, causing B cell activation. And then, the T cell also produces IL-2, which directly influences B cells. As a result of this net stimulation, the B cell can undergo division, antibody isotype switching, and differentiation to plasma cells. The end-result is a B cell that is able to mass-produce specific antibodies against an antigenic target. Besides, CD40 widely expresses on normal cells and tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell haematopoiesis.

Clinical significance

Because interaction of CD154 and CD40 has a key role in initiating alloimmune response and graft survival, subsequent to CD28, CD154-CD40 interactions are perhaps the most well-studied pathway in transplantation. Inhibition of CD154-CD40 interactions diminishes innate immune responses to transplanted tissue, resulting in diminished expansion and differentiation of allospecific CD4+ and CD8+ effector T cells. In addition to this potent effect on effector T cell responses, CD154 antagonism promotes conversion of conventional CD4+ T cells into Foxp3+ peripheral Treg cells and increases accumulation of Treg cells within the allograft and subsequently in the graft-draining LN. Evidence also exists to suggest that antagonism of CD154-CD40 interactions results in the upregulation of coinhibitory molecules on donor-reactive T cell populations, such as PD-1, KLRG-1, and TIM-3. CD154-CD40 interactions are also critical for the development of donor-specific antibody and antibody-mediated rejection, and therapeutic blockade of this pathway diminishes the development of alloreactive B cell germinal center responses in mice and mitigates antibody-mediated rejection of kidney allografts in non-human primates. Further, blockade of the CD154-CD40 pathway is perhaps the most potent method of long-term tolerance induction yet identified in experimental models of transplantation, in that recipient exposure to resting hematopoietic donor cells in the presence of CD154-CD40 blocking reagents has been shown to result in durable tolerance to skin, heart, and islet transplantation. It is interesting to note that this CD8+ T cell-intrinsic role for CD40-mediated costimulation was found not to play a role in the generation of pathogenelicited CD8+ T cell responses, highlighting a potential difference in the costimulatory requirements during alloimmune responses versus protective immunity. A potential explanation for this difference is the fact that ligation of Toll-like receptors (TLRs) expressed on CD8+ T cells in the setting of pathogen infection could compensate for the requirement for T cell-intrinsic CD40 signals. In addition, CD154 has proven to be expressed on CD11c+ DC following TLR ligation. Thus, while this pathway is likely to play during pathogen infection, the role of DC-derived CD154 in the execution of alloreactive immune responses remains to be determined. Lastly, the discovery that CD154 likely has another binding partner—CD11b (Mac-1) —sheds significant light on the mechanism by which CD154 blockade potently inhibits aspects of innate cell recruitment during transplantation. While the contribution of CD154-CD11b interactions to the development of alloimmunity remains an unexplored area, the potential role of this interaction will likely enter into the calculus of whether CD154 or CD40-directed reagents are likely to provide more favorable results for immune modulation in the setting of transplantation. Given the numerous and potent effects of therapeutic targeting of CD154-CD40 interactions in the setting of alloimmunity, interest in development of pharmacologic inhibitors for translation into clinical transplantation remains high. While early clinical trials were stymied by thromboembolic complications associated with the use of anti-CD154 reagents owing to the expression of CD154 on platelets, recent technological developments have resulted in the generation of potentially clinically translatable reagents for targeting this pathway. First, non-agonistic anti-CD40 antibodies are being developed in order to avoid the use of anti-CD154-associated coagulopathic events. With the increasing of understanding of CD154-CD40 pathway, a phase IIa clinical trial of an anti-CD40 mAb (ASKP1240) is currently underway for use in kidney transplantation, and therapeutic manipulation of the CD154-CD40 pathway in order to improve outcomes in transplantation might eventually become a clinical reality. The results of this trial will be very informative in evaluating the potential of harnessing this pathway to improve clinical outcomes in transplantation, and potentially autoimmunity.

The CD40/CD40L system is implicated in proinflammatory pathways and is expressed in a variety of cells such as immunity cells, the vascular wall and platelets. This means that this pathway may relate to tumor production. In clinical studies, patients with different cancers exhibit higher circulating sCD40L (the soluble form of CD40 ligand) levels, so sCD40L may serve as a useful biomarker of tumor. However, it remains unclear whether sCD40L can be used as a therapeutic target in carcinogenesis, as circulating sCD40L levels may only  represent platelet activation. Therefore, there are a lot of clinical trials to elucidate the potential use of sCD40L as a reliable biomarker and therapeutic target in cancer treatment.

References:

  1. Mandy L. F., T Cell Cosignaling Molecules in Transplantation. Immunity, 2016, 44:1020-1033.
  2. Mandy L. F., et al. Targeting co-stimulatory pathways: transplantation and autoimmunity. Nature, 2014, 10: 14-24.
  3. Anastasios A., et al. The Role of Soluble CD40L Ligand in Human Carcinogenesis. Anticancer Research,2018, 38: 3199-3201.

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