CD40/CD40 ligand interactions in immune responses and pulmonary immunity

Abstract

The CD40 ligand/CD40 pathway is widely recognized for its prominent role in immune regulation and homeostasis. CD40, a member of the tumor necrosis factor receptor family, is expressed by antigen-presenting cells, as well as non-immune cells and tumors. The engagement of the CD40 and CD40 ligands, which are transiently expressed on T cells and other non-immune cells under inflammatory conditions, regulates a wide spectrum of molecular and cellular processes, including the initiation and progression of cellular and humoral adaptive immunity. Based on recent research findings, the engagement of the CD40 with a deregulated amount of CD40 ligand has been implicated in a number of inflammatory diseases. We will discuss the involvement of the CD40 ligand/CD40 interaction in the pathophysiology of inflammatory diseases, including autoimmune diseases, atherothrombosis, cancer, and respiratory diseases.

Fig. 1

B cell activation during cognate interactions with T cells and antigen-driven B cell differentiation. Engagement of CD40 on antigen-driven B cells undergoes clonal expansion, and their immunoglobulin genes undergo two unique alterations: class switch recombination and affinity maturation through somatic hypermutation and selection. These cellular and molecular processes promote antibody production (plasma cells) and the development of high-affinity B cell memory in response to foreign antigen exposure. TCR, T-cell receptor; MHC, major histocompatibility complex; AID, activation-induced cytidine deaminase; UNG, uracil-DNA glycosylase.

Fig. 2

Pleiotropic effects resulting from the interaction between CD40L (on T cells and platelets, or in soluble form) and CD40 on immune or non-immune cells. When activated through the CD40 pathway, dendritic cells, macrophages, and monocytes induce a rather wide range of effects, which include the production of cytokines, cyclooxygenases (COX), an inducible nitric oxide synthase (iNOS), matrix metalloproteinases (MMPs), and an upregulation of cell adhesion molecules. Activation of non-immune cells through the CD40 pathway induces a spectrum of effects similar to those observed in monocytic cells.

Fig. 3

Immunoregulation of surfactant-associated protein (SP) production in alveoli. Type II alveolar epithelial cells produce four SPs (SP-A, SP-B, SP-C, and SP-D). SP-A and SP-D, which belong to a collectin subgroup as pulmonary collectins, orchestrate innate immunity in the lung. After acquired immunity has supervened, type II alveolar epithelial cells markedly lower the production of SPs by the interaction of CD40 on themselves with CD154 on activated T cells.