Lec 11 MHC and Antigen Presentation

Overview

In immunology, the Major Histocompatibility Complex (MHC) plays a critical role in the immune system by presenting antigens to T cells, which is essential for initiating and regulating the adaptive immune response. This document provides an in-depth examination of the structure and function of MHC molecules, the mechanisms of antigen processing and presentation, and the genetic basis of MHC diversity, which is crucial for effective immune responses and individual susceptibility to diseases.

Learning Outcomes

By the end of this learning activity, students should be able to:

• Describe the function, distribution, and structure of MHC molecules, including their role in antigen recognition and activation of T cells.

• Explain the processes of antigen processing, detailing how various proteins are converted into peptides suitable for MHC presentation, and how MHC molecules interact with T cell receptors during this process.

• Understand the MHC gene complex, including its chromosomal location, organization, and the mechanisms that promote MHC diversity, which influences susceptibility to diseases and transplant compatibility.

• Describe superantigens, their unique properties compared to regular antigens, and their mechanisms of pathogenesis, including diseases they can cause.

Antigens and T Cells

T cells are essential components of the adaptive immune response, equipped with T cell receptors (TCRs) that specifically recognize processed antigenic peptides presented by MHC molecules rather than free-floating antigens. Antigen-presenting cells (APCs)—which include dendritic cells, macrophages, and B cells—play a key role by processing proteins into short peptides. Dendritic cells are particularly pivotal, as they are responsible for capturing antigens, processing them, and presenting them to naive T cells in lymphoid tissues, thus facilitating the activation of T cells. The specific recognition and binding of peptide-MHC complexes by TCRs enable T cell activation, proliferation, and differentiation into effector cells that carry out immune functions.

Structure of T Cell Receptors (TCR)

TCRs are primarily composed of two chains: alpha (α) and beta (β). In a smaller subset of T cells, TCRs can consist of gamma (γ) and delta (δ) chains. Each T cell generates unique TCR chains, which contributes to the vast diversity of TCRs present within the immune repertoire through a process known as somatic recombination. Unlike B cells, T cells do not secrete their antigen receptors as antibodies. Both the α and β chains contain three hypervariable regions (known as Complementarity Determining Regions, CDRs), with CDR3 being particularly critical for the recognition of peptide-MHC complexes, while CDR2 primarily engages with MHC molecules during this interaction, stabilizing the binding.

MHC Molecule Classification

MHC molecules are classified into two main classes:

• Class I MHC molecules are expressed on almost all nucleated cells, and they present endogenous antigens (typically derived from proteins synthesized within the cell, such as viral or tumor antigens) to CD8+ cytotoxic T cells. These molecules serve as a surveillance mechanism for detecting intracellular pathogens and abnormal cells.

• Class II MHC molecules are predominantly expressed on professional antigen-presenting cells (APCs) such as dendritic cells, B cells, and macrophages. They present exogenous antigens (derived from extracellular sources) to CD4+ helper T cells, which play a crucial role in orchestrating the immune response, including antibody production and activation of other immune cells.

MHC Structure

• Class I MHC consists of a transmembrane alpha chain associated with β2-microglobulin, creating a peptide binding groove that is essential for peptide attachment. This groove accommodates peptides of approximately 7 to 10 amino acids in length.

• Class II MHC is composed of two transmembrane proteins, the alpha (α) and beta (β) chains, which together form a peptide-binding cleft that typically accommodates longer peptides ranging from 13 to 17 amino acids. The structure of Class II MHC allows for greater variability in the peptide binding, enhancing its ability to present diverse antigens.

Antigen Processing and Presentation

Class I MHC Processing

1. Endogenous antigens (such as viral proteins or mutated self-proteins in cancer) are degraded by the proteasome in the cytoplasm, resulting in the generation of short peptides that typically range from 7 to 12 amino acids in length.

2. These peptides are transported into the endoplasmic reticulum (ER) by the Transporter associated with Antigen Processing (TAP), which is crucial for loading peptides onto MHC Class I molecules.

3. MHC Class I molecules must bind a peptide in the ER to stabilize their conformation and facilitate their transport to the Golgi apparatus and ultimately the cell surface, where they present peptide antigens to CD8+ T cells.

Class II MHC Processing

1. Exogenous antigens are internalized by APCs through mechanisms such as receptor-mediated endocytosis. Once inside, these antigens are broken down into smaller peptide fragments within acidic endosomes via the action of proteolytic enzymes, including acid-dependent proteases.

2. Newly synthesized MHC Class II molecules from the ER initially contain an invariant chain that occupies the peptide-binding site to prevent premature binding of endogenous peptides. This invariant chain also helps in guiding MHC Class II to the endosomal compartments.

3. Within the endosome, the invariant chain is cleaved, retaining a portion called CLIP that must be exchanged for antigenic peptides. This exchange is facilitated by the actions of HLA-DM, which assists in releasing CLIP and stabilizing the binding of antigenic peptides to MHC Class II molecules, which are then transported to the cell surface to present to CD4+ T cells.

MHC Gene Complex

The MHC gene complex is located on chromosome 6 in humans and contains a large number of genes (over 200), which encode not only MHC molecules but also proteins involved in antigen processing and presentation, including TAP and other chaperones. This complex is divided into three primary subgroups:

1. Subgroup 1: Encodes Class I MHC molecules and associated proteins necessary for antigen presentation and processing.

2. Subgroup 2: Encodes Class II MHC molecules and various elements that assist in the processing of exogenous antigens.

3. Subgroup 3: Contains genes that encode a variety of immune response-related proteins, including cytokines and chemokines that mediate immune signaling.

Both polygenic (multiple genes contribute to traits) and polymorphic (multiple alleles for each gene exist), MHC diversity is essential for enabling the immune system to recognize a wide array of pathogens. Certain MHC alleles are associated with higher susceptibility to autoimmune diseases, highlighting the importance of MHC in both health and disease.

Superantigens

Superantigens are a unique class of antigens that can bind directly to the variable regions of many T cell receptors, triggering an extensive and non-specific activation of T cells. This can activate between 2% to 20% of T lymphocytes, leading to a massive release of cytokines, which can result in systemic inflammatory responses and significant pathologies. Conditions such as toxic shock syndrome, often driven by superantigens produced by certain staphylococcal toxins, exemplify the profound impact these antigens can have on host health, leading to severe clinical manifestations such as fever, rash, and multiple organ failure.

Summary of Differences in Antigen Processing