Epithelial MHC Class II Expression and Its Role in Antigen Presentation in the Gastrointestinal and Respiratory Tracts

Abstract

As the primary barrier between an organism and its environment, epithelial cells are well-positioned to regulate tolerance while preserving immunity against pathogens. Class II major histocompatibility complex molecules (MHC class II) are highly expressed on the surface of epithelial cells (ECs) in both the lung and intestine, although the functional consequences of this expression are not fully understood. Here, we summarize current information regarding the interactions that regulate the expression of EC MHC class II in health and disease. We then evaluate the potential role of EC as non-professional antigen presenting cells. Finally, we explore future areas of study and the potential contribution of epithelial surfaces to gut-lung crosstalk.

Keywords: MHC class II; antigen presentation; epithelial cells; intestine; respiratory.

Figure 1

Overview of MHC Class II Antigen Presentation Pathway. Newly synthesized MHC class II α and β chains assemble into heterodimers in the endoplasmic reticulum, where they are bound by trimers of invariant chain. MHC class II and invariant chain form nonamers–or, according to recent studies, pentamers and heptamers–that traffic into an acidic endosomal compartment. Within this compartment, invariant chain is degraded down to class II invariant chain-associated peptide (CLIP), which occupies the peptide binding groove of the MHC class II molecule. HLA-DM, a non-classical MHC protein, catalyzes the removal of CLIP in exchange for high-affinity peptide binders derived from extracellular or cytosolic antigens. In a subset of antigen presenting cells, HLA-DM is blocked by HLA-DO, which competitively binds to HLA-DM and prevents it from interacting with MHC class II. Once loaded with peptide, MHC class II molecules traffic to the plasma membrane for inspection by CD4⁺ T cells.

Figure 2

Intestinal Epithelial Cell MHC Class II Expression in Health and Disease. At homeostasis (left), MHC class II is constitutively expressed in the upper villi of the small intestine. At the crypt base, intestinal stem cells self-renew and differentiate into specialized cell types: antimicrobial-producing Paneth cells, mucus-producing Goblet cells, hormone-producing enteroendocrine cells, and nutrient-absorptive enterocytes (200). Healthy crypts lack MHC class II expression. Intraepithelial lymphocytes, consisting of T cells and γδ T cells, likely play a key role in maintaining the baseline expression of MHC class II in ECs by producing IFNγ. During disease (right), MHC class II levels increase and extend into the crypts. Epithelial barrier integrity decreases, which may result in ECs encountering antigen along both the apical and basolateral surfaces. Organized lymphoid structures, known as Peyer's Patches, contain dense concentrations of professional antigen presenting cells (B cells, macrophages, dendritic cells). These cells encounter antigen delivered by microfold (M) cells, which transcytose luminal antigens. Whereas MHC class II expression has been shown in the Peyer's Patch epithelium, there are conflicting reports regarding MHC class II expression by M cells.

Figure 3

EC MHC Class II Expression in the Lung During Homeostasis. The airway is composed of the upper airway conducting zone for humidifying and clearing particulates of inhaled air (bronchi and bronchioles) and lower airway respiratory zone for gas exchange (respiratory bronchioles and alveoli). At homeostasis, MHC class II expression has been seen in the ciliated ECs of the upper airway and in Type II pneumocytes of the alveoli. The polarity of class II expression is not well-defined. Unlike the intestine, organized lymphoid structures are not found in adulthood, except in disease states.