MHC/HLA and T Cell Antigen Recognition

Major Histocompatibility Complex (MHC) and Human Leukocyte Antigen (HLA)

• Definition and Relationship:

  • MHC (Major Histocompatibility Complex) is a gene complex found in all mammals.
  • HLA (Human Leukocyte Antigen) is the human-specific nomenclature for MHC.
  • They are functionally the same, differing only in their naming convention for humans.

• Types of MHC/HLA:

  • MHC Class I / HLA Class I:
    • Primarily recognized by Cytotoxic T Lymphocytes (CTLs), also known as CD$8$ T cells.
    • HLA Class I molecules are designated with a single letter (e.g., HLA-A, HLA-B, HLA-C).
    • CD$8$ co-receptor on CTLs binds to the $\alpha3$ domain of the MHC Class I molecule.
  • MHC Class II / HLA Class II:
    • Primarily recognized by T Helper (T_H) cells, also known as CD$4$ T cells.
    • HLA Class II molecules are designated with two letters (e.g., HLA-DM, HLA-DP, HLA-DQ, HLA-DR).
    • CD$4$ co-receptor on T_H cells binds to the $\beta2$ domain of the MHC Class II molecule.

T Cell Antigen Recognition

• Process:

  1. Antigen Processing: The breakdown of antigens into smaller peptide fragments.
  2. Antigen Presentation: The display of these peptide fragments by MHC molecules on the cell surface.

• Antigen-Presenting Cells (APCs):

  • MHC Class I is found on almost all nucleated cells, presenting intracellular antigens.
  • MHC Class II is primarily found on Professional Antigen-Presenting Cells (pAPCs).
  • Types of pAPCs:
    1. Dendritic cells: Highly efficient at initiating T cell responses.
    2. Macrophages: Phagocytic cells that engulf and present antigens.
    3. B cells: Can internalize antigens via their B cell receptor and present them.

• Clonal Selection: The process by which specific T cells (and B cells) are activated and proliferate upon encountering their specific antigen presented by MHC.

Peptide Loading Pathways

MHC Class I Pathway (Intracellular Infections)

• Purpose: Presents peptides derived from proteins synthesized in the cytosol, typically indicating intracellular infections (e.g., viral infections, some bacterial infections) or cellular abnormalities (e.g., tumor cells).
• **Steps (as depicted in Figure 5.20):
  1. Antigen Degradation: Proteins in the cytosol (normal self-proteins or foreign proteins from pathogens) are degraded into peptide fragments by the proteasome.
  2. ER Entry: These peptide fragments are transported from the cytosol into the endoplasmic reticulum (ER) lumen by the TAP (Transporter Associated with Antigen Processing) complex.
  3. MHC Class I Assembly Primer: The MHC Class I heavy chain is synthesized in the ER and initially stabilized by the chaperone calnexin until $\beta2$-microglobulin ($\beta2$m) binds.
  4. Peptide-Loading Complex Formation: Upon $\beta2$m binding, calnexin is released. The MHC Class I heavy chain/$\beta2$m heterodimer then associates with a peptide-loading complex containing calreticulin, tapasin, ERp57, and TAP.
  5. Peptide Binding: Peptides delivered by TAP bind to the MHC Class I heavy chain. Tapasin helps to optimize peptide binding.
  6. MHC Maturation: Once a peptide is successfully bound with high affinity, the mature MHC Class I molecule dissociates from the loading complex.
  7. Surface Expression: The stable MHC Class I-peptide complex is then exported from the ER and transported to the cell surface for presentation to CD$8$ T cells.

MHC Class II Pathway (Extracellular Infections)

• Purpose: Presents peptides derived from proteins taken up from the extracellular environment, typically indicating extracellular bacterial infections or toxins.
• **Steps (as depicted in Figures 5.22 & 5.23):
  1. Antigen Uptake: Antigens from the extracellular space are internalized by endocytosis into intracellular vesicles (endosomes) by pAPCs.
  2. Antigen Degradation: Within these vesicles:
     • Early endosomes have neutral pH where proteases are inactive.
     • As endosomes mature and undergo acidification, endosomal proteases (e.g., cathepsins) become active and degrade the antigen into peptide fragments.
  3. MHC Class II Synthesis and Invariant Chain Association: MHC Class II molecules are synthesized in the ER and associate with a protein called the invariant chain (Ii).
     • The invariant chain's role is to prevent peptides from the MHC Class I pathway (those processed in the ER) from binding to MHC Class II molecules.
     • It also aids in the proper folding and exit of MHC Class II from the ER.
  4. Vesicle Translocation and Invariant Chain Cleavage: The MHC Class II-Ii complex exits the ER and moves into the endosomal pathway where antigen degradation is occurring. In these vesicles, the invariant chain is proteolytically cleaved, leaving a small fragment called CLIP (Class II-associated Invariant chain Peptide) bound to the MHC Class II peptide-binding groove.
  5. Peptide Exchange (CLIP Release): HLA-DM, a non-classical MHC Class II molecule, acts as a chaperone. It facilitates the release of the CLIP fragment from MHC Class II, creating an empty binding groove.
  6. Antigenic Peptide Binding: This empty groove allows peptides generated from the degradation of internalized antigens to bind to the MHC Class II molecule.
  7. Surface Expression: Vesicles containing the stable MHC Class II-peptide complexes then fuse with the plasma membrane, presenting the peptide on the cell surface to CD$4$ T cells.

Genetic Polymorphisms of HLA

• High Variability: HLA genes are highly polymorphic, meaning there are many different alleles (variants) within the human population at each locus.
• Significance: This polymorphism is crucial for the immune system to recognize a vast array of pathogens. Individuals with different HLA alleles will present different sets of peptides, leading to varying immune responses.
• **HLA Class I Isotypes (Figure 5.28 & 5.29):
  • HLA-A: Highly polymorphic ($1939$ allotypes).
  • HLA-B: Highly polymorphic ($2577$ allotypes).
  • HLA-C: Highly polymorphic ($1595$ allotypes).
  • HLA-E: Oligomorphic ($6$ allotypes) - presents specific peptides to NK cells.
  • HLA-F: Monomorphic ($4$ allotypes) - intracellular, regulatory role.
  • HLA-G: Oligomorphic ($16$ allotypes) - involved in immune tolerance at the maternal-fetal interface.
• **HLA Class II Isotypes (Figure 5.29):
  • HLA-DM (DMA, DMB): Polymorphic ($47$ allotypes for DMa, $4$ for DMb). Acts as a peptide editor.
  • HLA-DO (DOA, DOB): Polymorphic ($3$ for DOA, $5$ for DOB). Regulates HLA-DM activity.
  • HLA-DP (DPA1, DPB1): Highly polymorphic ($17$ for DPa1, $286$ for DPb1).
  • HLA-DQ (DQA1, DQB1): Highly polymorphic ($32$ for DQa1, $399$ for DQb1).
  • HLA-DR (DRA, DRB1, DRB3, DRB4, DRB5): Highly polymorphic, especially DRB1 ($2$ for DRa, $1158$ for DRb1, $46$ for DRb3, $8$ for DRb4, $17$ for DRb5). DRA is largely monomorphic, while DRB genes are highly polymorphic and determine peptide specificity.

Peptide Binding Motif (Anchor Residues)

• Specific Binding: MHC molecules do not bind just any peptide; they bind peptides that fit a specific peptide-binding motif.
• Anchor Residues: These are specific amino acid residues within the peptide sequence, usually at particular positions (e.g., position $2$ and position $9$ for MHC Class I), that interact directly and strongly with pockets within the MHC binding groove. These