Study Notes on Major Histocompatibility Complex (MHC) and Natural Killer (NK) Cells

Lecture 8: MHC Structure, Function, and Genes

Textbook references:

  • Kuby: Chapters 7 (MHC) and 12 (NK and NKT)

  • Parham: Components of Chapters 5 and 12 (Figures from Parham unless otherwise indicated)

Learning Objectives

  • Compare and contrast MHC I, II, and III in mice and humans, including their functions.

  • Describe the major structural features of MHC I and II.

  • Describe the prototypical genes in each of the MHC complexes.

  • Describe the organization and inheritance of MHC genes.

  • Describe prototypical and secondary MHC genes.

  • Describe how MHC interacts with target cells.

MHC Critical Role in Antigen Presentation

Basic Steps:

  1. Pathogen protein enters a human cell.

  2. Antigen processing occurs via the breakdown of the protein.

  3. Presentation of peptide occurs by MHC molecules.

  4. Recognition of the antigen:MHC complex by T-cell receptor (TCR).

Major Histocompatibility Complex (MHC)

  • Definition: A cluster of genes located on a single chromosome (chromosome 6 in humans, chromosome 17 in mice) coding for cell-surface molecules that present antigens to T cells and immune proteins.

  • Functions:

    • Present antigens to T cells.

    • Engage NK cells via self vs. missing self recognition.

  • Alternate Names: Human Leukocyte Antigens (HLA) in humans and H2 complex in mice.

  • Classes of MHC:

    1. Class I

    2. Class II

    3. Class III

  • Chromosomal Location:

    • Class I: Chromosome 17

    • Class II: Chromosome 6

MHC III Complex

  • Function: Does NOT present antigens (unlike MHC I and II).

  • Encodes:

    • Complement proteins.

    • Inflammatory mediators such as TNF and lymphotoxin.

Types of MHC

  • Three types exist (MHC I, II, and III), but only MHC I and II present antigens.

MHC I and II Expression by Cell Type

  • Expression Levels:

    • Hematopoietic Cells:

    • T cells: Class I (+++), Class II (+)

    • B cells: Class I (+++), Class II (+++)

    • Macrophages: Class I (+++), Class II (++)

    • Dendritic cells: Class I (+++), Class II (+++)

    • Neutrophils: Class I (+++), Class II (-)

    • Erythrocytes: Class I (+++), Class II (-)

    • Non-Hematopoietic Cells:

    • Liver hepatocytes: Class I (+), Class II (-)

    • Kidney epithelium: Class I (+), Class II (-)

    • Brain: Class I (+), Class II (-)

MHC Peptide Presentation

  • MHC I:

    • Presents peptides derived from within the cell (i.e., endogenous).

  • MHC II:

    • Presents peptides derived from outside the cell (i.e., exogenous).

  • Cross-Presentation:

    • Occasionally, peptides can be cross-presented from outside the cell on MHC I.

MHC I Structure and Components

  • Overview:

    • MHC I consists of a peptide nestled between alpha-helices and requires beta-2-microglobulin for stabilization.

  • Conserved Regions:

    • Transmembrane Domain:

    • 45 kDa α chain peptide linked noncovalently to a 12 kDa β2 microglobulin molecule.

    • Organized into 3 globular domains (external), a hydrophobic sequence (membrane anchor), and a short hydrophilic sequence (cytoplasmic).

    • α3 Domain:

    • Highly conserved; interacts noncovalently with β2 microglobulin and the CD8 co-receptor on CTLs.

    • β2m (Beta-2-microglobulin):

    • Interacts with α3 domain, stabilizing MHC I complexes.

MHC II Function and Structure

  • Function:

    • Presents antigens derived from the extracellular/exogenous compartment to CD4+ T cells.

    • Located on professional antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells.

  • Structure:

    • Composed of two glycoprotein chains (α - 33 kDa and β - 28 kDa).

    • Comprised of 2 external globular domains, one hydrophobic membrane anchor, and one hydrophilic cytoplasmic tail.

    • Variable regions: α1 and β1 form the antigen/peptide-binding groove.

      • Peptides are typically 13-18 amino acids long and protrude from the binding groove.

    • Conserved regions: α2 and β2 are relatively conserved among MHC II molecules.

MHC Peptide Binding Dynamics


  • Table 7-1: Peptide Binding by MHC Class I and II Molecules

    Peptide-binding domain

    Nature of Peptide-binding

    General Size of Bound Peptides

    Anchor Residues

    Nature of Bound Peptide


    Class I (α1/a2)

    Closed at both ends

    8-10 amino acids

    Anchor residues at both ends of peptide; generally hydrophobic at carboxy-terminus

    Extended structure where both ends interact with MHC groove but middle arches up from MHC molecule


    Class II (α1/β1)

    Open at both ends

    13-18 amino acids

    Conserved residues distributed along the peptide anchor

    Extended structure that is held above the MHC groove floor.

    MHC Gene Inheritance and Polymorphism

    • Haplotypes:

      • Genes arranged in haplotypes influence co-inheritance patterns; genes closer together are more likely to be inherited together.

    • MHC Polymorphism:

      • MHC is the most polymorphic gene in the human genome.

      • Influences T cell repertoire diversity and the likelihood of transplantation rejection reactions.

      • Polymorphism ensures diversity in peptide presentation and enables populations to respond to a larger variety of pathogens.

    • Heterozygote Advantage:

      • Increases antigen presentation likelihood via multiple alleles at MHC loci.

    MHC and Disease Susceptibility

    • A reduction in MHC polymorphism may predispose species to disease by limiting interaction range with processed antigens.

    • Some MHC alleles might provide binding sites for pathogens, affecting immune response efficacy.

    • Variations in antigen presentation across MHC alleles can determine susceptibility to diseases, including autoimmune disorders.

    NK Cells Overview

    • Definition: Natural Killer (NK) cells are nonspecific cytotoxic effector cells making up 5-10% of peripheral blood lymphocytes; they are essential in early defenses against viruses and cancers.

    • Development: NK cells develop from the same progenitors as T cells but do not exclusively mature in the thymus.

    • Recognition Mechanism:

      • Lacks MHC restriction; can exhibit immunologic memory.

      • Crucial source of IFN-γ, enhancing macrophage activity and influencing adaptive immunity by promoting Th1 differentiation and CTL development.

    NK Cell Functions and Mechanisms of Action

    • Cytotoxic Mechanism:

      • Polarization of cytotoxic granules towards the target cell leads to exocytosis of granzyme B and perforin after triggering via activating receptors.

      • Triggering of death receptors on target cells can lead to apoptosis.

    • Cytokine Activation: IFN-α and IFN-β activate NK cells, augmenting antiviral activity.

    Interaction Between T Cells and NK Cells

    • T cells and NK mediated cytotoxicity have complementary roles in immune responses.

    • Missing Self Recognition:

      • Target cells with low MHC class I expression are killed by NK cells.

      • NK cells see a lack of MHC/HLA as a trigger for activation, while normal MHC expression inhibits NK cell activity.

    MHC and NK Cell Interactions

    • NK cells bind to conserved epitopes found in HLA (MHC) and react to allosteric changes from bound peptides rather than specific antigen binding.

    • Variability in HLA leads to different responses from NK cells due to their multiple KIRs allowing them to recognize numerous HLA variants.

    Non-Classical MHC Molecules

    • Class I:

      • Reduced expression specific to certain tissues (e.g., HLA-G for fetal tolerance).

      • HLA-E facilitates NK cell interactions.

    • Class II:

      • Less polymorphic; functions primarily in peptide loading assistance and antigen presentation regulation (e.g., HLA-DM).

    Conclusion

    • The complex structure, diversity, and function of the MHC are critical for effective immune responses, influencing susceptibility to disease and the interplay between various immune cell types.

    • MHC polymorphism offers a safeguard against pathogen evasion, maintaining robust immune surveillance.