Major Histocompatibility Complex (MHC) Class I Complexes

The Major Histocompatibility Complex (MHC) is a set of cell-surface proteins essential for the adaptive immune system to recognize foreign molecules. MHC molecules are classified into two primary categories: Class I and Class II, each with distinct structures, expression patterns, and functions. MHC Class I complexes are central to the immune response against intracellular pathogens, such as viruses and some bacteria, and in tumour surveillance.

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Structure of MHC Class I Complexes

An MHC Class I molecule is a heterodimer, composed of two polypeptides:

1. α (alpha) chain:

   • Approximately 45 kDa.

   • Encoded by HLA-A, HLA-B, and HLA-C genes in humans (HLA = human leukocyte antigen).

   • Comprises three extracellular domains:

     • α1 and α2 domains: Form the peptide-binding groove, which accommodates short peptides (typically 8–10 amino acids in length).

     • α3 domain: A conserved Ig-like domain that interacts with CD8 co-receptors on cytotoxic T lymphocytes (CTLs).

   • A transmembrane region anchors the molecule in the plasma membrane.

   • A cytoplasmic tail assists in intracellular trafficking.

2. β2-microglobulin (β2m):

   • Approximately 12 kDa.

   • Not encoded within the MHC locus.

   • Associates non-covalently with the α chain.

   • Essential for structural stability and cell surface expression.

The peptide-binding groove of MHC Class I molecules is closed at both ends, which restricts the length of bound peptides to 8–10 amino acids, though longer peptides may bulge out of the groove. Peptide binding is highly allele-specific, governed by “anchor residues” that interact with pockets in the groove.

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Expression of MHC Class I

• Ubiquitous expression: MHC Class I molecules are expressed on almost all nucleated cells, providing a mechanism for cytotoxic T cells to monitor intracellular health.

• Absent on red blood cells: Mature erythrocytes lack nuclei and, therefore, do not express MHC Class I.

• Inducible expression: Cytokines, especially interferons (IFN-α, IFN-β, IFN-γ), upregulate MHC Class I expression to enhance immune surveillance during infection.

• Allelic polymorphism: Each individual inherits a set of MHC Class I alleles from each parent, resulting in extensive diversity and enabling the population to present a wide array of pathogenic peptides.

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Peptide Processing and Loading

MHC Class I molecules present endogenous peptides, derived from cytosolic proteins, to CD8+ cytotoxic T lymphocytes (CTLs). The pathway involves several key steps:

1. Protein degradation:

   • Cytosolic proteins, including viral proteins or aberrant self-proteins, are tagged with ubiquitin.

   • These proteins are degraded by the proteasome into short peptides.

   • The immunoproteasome, induced by IFN-γ, generates peptides with optimal lengths and anchor residues for MHC Class I binding.

2. Peptide transport:

   • Peptides are translocated from the cytosol into the endoplasmic reticulum (ER) via the Transporter Associated with Antigen Processing (TAP1/TAP2).

3. Peptide loading:

   • Within the ER, MHC Class I α chains and β2-microglobulin associate with a set of chaperone proteins, forming the peptide-loading complex (PLC):

     • Calnexin stabilizes the α chain before β2m binding.

     • Calreticulin assists in final folding.

     • ERp57 and tapasin facilitate peptide binding to the α1/α2 groove.

   • Only peptides with sufficient affinity are retained; suboptimal peptides are replaced.

4. Transport to the cell surface:

   • Once stably loaded, the MHC Class I–peptide complex is transported through the Golgi apparatus to the plasma membrane, where it is displayed for T cell surveillance.

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Interaction with CD8+ T Cells

• Cytotoxic T lymphocytes (CD8+ T cells) recognize antigenic peptides presented by MHC Class I molecules via their T cell receptor (TCR).

• The CD8 co-receptor binds to the α3 domain of MHC Class I, stabilizing the interaction.

• If the peptide is recognized as non-self (e.g., viral), the CTL initiates target cell apoptosis using:

  • Perforin/granzyme pathway.

  • Fas-FasL pathway.

• This mechanism is essential for viral clearance, tumour immunosurveillance, and elimination of infected or transformed cells.

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Role in Immune Evasion and Disease

Many pathogens and tumours have evolved strategies to evade MHC Class I presentation:

1. Viral strategies:

   • Herpesviruses (e.g., CMV, HSV): Encode proteins that block TAP or retain MHC Class I in the ER.

   • Adenoviruses: Promote MHC Class I degradation.

2. tumour cells:

   • Downregulate MHC Class I to avoid CTL detection.

   • Often recognized by natural killer (NK) cells, which target cells with low MHC Class I (“missing self” hypothesis).

Clinical relevance:

• Defects in MHC Class I can lead to immunodeficiency, impaired viral clearance, or cancer susceptibility.

• Overexpression can contribute to autoimmune diseases by presenting self-peptides to autoreactive T cells.

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Polymorphism and Genetics

• Highly polymorphic loci: HLA-A, HLA-B, and HLA-C genes are extremely variable within the population.

• Importance:

  • Allows presentation of diverse peptides across individuals.

  • Affects transplant compatibility: MHC Class I mismatches lead to graft rejection.

  • Certain alleles correlate with susceptibility to infections or autoimmune diseases (e.g., HLA-B27 and ankylosing spondylitis).

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Experimental and Clinical Applications

1. Transplantation:

   • MHC Class I typing is essential to minimize graft rejection.

2. Vaccine design:

   • Peptide vaccines aim to induce CD8+ T cell responses by targeting MHC Class I presentation.

3. Cancer immunotherapy:

   • TCR-engineered T cells recognize tumour peptides presented by MHC Class I.

   • Immune checkpoint inhibitors enhance CTL activity against MHC Class I-restricted antigens.

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Summary of Key Points

• MHC Class I molecules present intracellular peptides to CD8+ T cells.

• They are heterodimers of an α chain and β2-microglobulin.

• Expressed on almost all nucleated cells, with variable expression influenced by cytokines.

• Peptides are generated in the cytosol, transported to the ER by TAP, loaded onto MHC I with chaperones, and displayed on the cell surface.

• Recognition by CD8+ T cells triggers targeted cell death.

• Polymorphism in HLA genes ensures population-level peptide diversity.

• Pathogens and tumours exploit MHC Class I downregulation to evade immune detection.

• Clinically important in infection, cancer, autoimmunity, and transplantation.

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In conclusion, MHC Class I complexes are central to cellular immunity, linking intracellular antigen detection to the adaptive immune response. Their intricate processing, peptide-binding specificity, and interaction with CD8+ T cells make them critical for defending against viruses, tumours, and intracellular pathogens. Dysregulation or evasion of MHC Class I presentation can result in severe infections, malignancies, or immunological disorders, highlighting their clinical and therapeutic significance.