Chapter 7

Chapter 7: The Major Histocompatibility Complex and Antigen Presentation

Introduction

The Major Histocompatibility Complex (MHC) is a critical component of the immune response, playing a vital role in the detection of pathogens and the activation of immune cells, particularly T cells. Understanding the structure, function, and genetic variability of MHC is essential for comprehending various immune responses and implications in transplantation and autoimmunity.

Structure and Function of MHC Class I and II Molecules

MHC Class I Molecules

  • Family: Member of the immunoglobulin (Ig) superfamily.

  • Proteins Involved:

    • β2-microglobulin: A smaller protein weighing approximately 12 kDa.

    • α chain: A larger glycoprotein, about 45 kDa.

  • Domain Structure:

    • Composed of three external domains, each approximately 90 amino acids in length.

    • Includes a transmembrane domain of about 25 amino acids and a cytoplasmic anchor consisting of 30 amino acids.

  • Peptide-binding Cleft: This cleft, formed by the α chain and β2-microglobulin, accommodates peptides typically of 8-10 amino acids in length. The structural design features a β sheet that creates a floor, with two α helices forming the walls of the cleft.

MHC Class II Molecules

  • Family: Also a member of the Ig superfamily.

  • Proteins Involved:

    • α chain: Weighs around 33 kDa.

    • β chain: Weighs about 28 kDa.

  • Domain Structure:

    • Both chains traverse the plasma membrane, creating a complex that is crucial for immune signaling.

    • The peptide-binding cleft, formed by the α1 and β1 domains, binds larger peptides of 13-18 amino acids in size. It has a similar foundational structure to MHC class I, with a β sheet forming the floor and α helices as walls.

Comparison of MHC Class I and II Structures

  • Peptide-binding Groove Differences:

    • MHC I: Closed at both ends, which facilitates a unique arch formation that anchors peptides in the middle. This configuration is essential for presenting endogenous antigens (those generated within the cell).

    • MHC II: Open at both ends, allowing for an overhang of peptides that are presented in a flat orientation. This configuration is essential as MHC II primarily presents exogenous antigens (those acquired from outside the cell).

MHC Polymorphism and Peptide Binding

Polymorphism Characteristics

  • Genetic Diversity: The MHC complex exhibits extensive polymorphism, with hundreds of allelic variants found in the human population. Individuals can express up to 6 class I and 12 class II molecules, leading to diverse presentations of antigenic peptides.

  • Diverse Binding Abilities: A single MHC molecule can bind numerous different peptides, and, conversely, some peptides can associate with multiple MHC molecules, enhancing the immune system's ability to recognize various pathogens.

Peptide Binding Mechanisms

  • Class I MHC-Peptide Interactions:

    • Presents endogenous peptides to CD8+ T cells. These peptides are derived from proteins synthesized within the cell and often signify the cellular health or infection state of the presenting cell.

  • Class II MHC-Peptide Interactions:

    • Engages CD4+ T cells by presenting exogenous peptides. These peptides are derived from extracellular proteins taken up by professional antigen-presenting cells (APCs).

Organization and Inheritance of MHC Genes

MHC Class Gene Overview

  • Class I MHC: Found on almost all nucleated cells in the body, these glycoproteins are pivotal in presenting endogenous antigens.

  • Class II MHC: Mainly expressed on antigen-presenting cells such as dendritic cells, macrophages, and B cells, these glycoproteins present exogenous antigens to immune cells.

  • Class III MHC: This class includes proteins not directly involved in peptide presentation, such as complement proteins, playing various roles in immune responses.

Genetic Inheritance

  • Haplotype Structure: MHC genes are inherited together as linked haplotypes due to their physical proximity on chromosomes.

  • Codominant Expression: The codominant expression of alleles results in a high degree of variability, which can pose challenges for organ transplantation due to the risk of rejection if donor and recipient MHC haplotypes are incompatible.

Critical Role of MHC in Immune Response

Antigen Presentation Importance

  • MHC molecules are essential for presenting self-proteins, which indicates cellular health and is a vital mechanism for immune tolerance, preventing autoimmunity.

  • The interaction with both CD8+ (cytotoxic) and CD4+ (helper) T cells is crucial for the activation of adaptive immunity and the orchestration of immune responses against pathogens.

  • MHC expression levels can be influenced by genetic regulatory components, cytokine signaling from infections, and viral strategies aimed at evading detection by immune cells.

Changes in MHC Expression

  • MHC Class I expression can be downregulated in response to certain viral infections, allowing viruses to escape immune surveillance. Conversely, upregulation can be induced by pro-inflammatory cytokines in response to infection, enhancing immune responses.

Antigen Processing Pathways

Endogenous Pathway for MHC Class I

  • Proteasomal Degradation: Proteins tagged for degradation are processed by the proteasome into peptides which are then transported into the Rough Endoplasmic Reticulum (RER) via Transporter associated with Antigen Processing (TAP).

  • Assembly and Stabilization: Chaperones assist during MHC class I assembly, ensuring that peptides are stably bound, allowing for effective antigen presentation to CD8+ T cells.

Exogenous Pathway for MHC Class II

  • Antigen Internalization: Antigens are taken up by APCs and processed within endosomal and lysosomal compartments, leading to peptide generation suitable for MHC class II binding.

  • Invariant Chain Function: An invariant chain facilitates the transport of MHC class II molecules to the endosomal compartment and blocks peptide binding until the appropriate exogenous peptide is available.

Cross-Presentation Mechanisms

Dendritic Cells as Primary Cross-Presenters

  • Dendritic cells can redirect exogenous antigens to MHC class I presentation pathways, crucial for eliciting CD8+ T cell responses against viruses. This process often requires “licensing” by cytokine signals received from helper T cells (CD4+ T cells).

  • This capability is pivotal in orchestrating immune memory and responses against pathogens that may not directly infect dendritic cells.

Recognition of Nonprotein Antigens

  • Some non-protein antigens, such as lipids, are recognized through CD1 and MR1 molecules. These specialized pathways enable the immune system to respond to a broader array of potential threats beyond just proteinaceous antigens.

Summary of Key Concepts

T cells require antigen presentation for activation, mediated through MHC molecules. Understanding the structure, function, processing pathways of MHC, and the implications of polymorphism is critical for comprehending T-cell activation and varying immune responses, essential for developing therapies against infectious diseases, cancer, and autoimmune disorders.