immunology

The Major Histocompatibility Complex and Antigen Presentation (Part 2)

Lecture Information

  • Topic: The Major Histocompatibility Complex and Antigen Presentation

  • Course: BIOB410/MB 510

  • Instructor: Kuby

  • Date: 2-19-26

Lecture Outline

  • MHC (Major Histocompatibility Complex)

  • MHC Expression

  • MHC Restriction

  • Class I Pathway

  • Class II Pathway

  • Cross Presentation

MHC Structure and Haplotype

  • Maternal and Paternal MHC Haplotype:

    • MHC Class I Molecules:

    • HLA-Am, HLA-Bm, HLA-Cm (maternal)

    • HLA-Ap, HLA-Bp, HLA-Cp (paternal)

    • MHC Class II Molecules:

    • HLA-DP (αmβm), HLA-DQ (αmβm), HLA-DR (αmβm) (maternal)

    • HLA-DP (αpβp), HLA-DQ (αpβp), HLA-DR (αpβp) (paternal)

    • HLA-DP (αmβp), HLA-DP (αpβm), HLA-DQ (αmβp)

    • HLA-DQ (αpβm), HLA-DR (αmβp), HLA-DR (αpβm)

  • Key:

    • m - maternal

    • p - paternal

Functions of MHC Molecules

MHC Class I

  • Role: Present antigens from intracellular locations

  • Indicators of Cell Health:

    • Presence of self peptides indicates a healthy cell.

    • Absence leads to recognition by NK cells as infected or tumor cells.

  • Mechanism:

    • Cytosolic foreign peptides presented on MHC I result in lysis by CD8+ T cells.

MHC Class II

  • Role: Present antigens from extracellular spaces

  • Expressed by: Antigen Presenting Cells (APCs)

  • Activation Functions:

    • Present antigens to TH (Helper T) cells

    • Help activate TC (Cytotoxic T) cells and B cells, facilitating antibody secretion against extracellular pathogens.

MHC Restriction

  • Definition: Self-MHC restriction involves the dual specificity for both self-MHC and foreign peptide.

  • Occurrence:

    • It occurs during positive selection of T cells in the thymus.

Research Highlights on MHC Restriction

  • Zinkernagel & Doherty’s Experiments (1970s):

    • Explored MHC restriction on CD8+ T cells that lyse virally infected cells.

    • Awarded the Nobel Prize in 1996 for their work.

    • Key Findings:

    • CD8 T cells are restricted; their T Cell Receptor (TCR) is specific for self MHC I + antigenic peptide (e.g., H-2b, H-2K).

    • References:

      • Zinkernagel RM, Doherty PC. Nature (1974); 248: 701-702

      • Doherty PC, Zinkernagel RM. J Exp Med (1975); 141: 502-7

Thymus and Self-MHC Restriction

  • Determination of MHC Restriction:

    • Thymus haplotype influences the recognition of peptides presented in the context of self-MHC alleles.

    • T cells “learn” their MHC restriction during processing in the thymus via positive selection.

    • Reference: Zinkernagel RM, et al. J Exp Med (1978); 147: 882-896.

Roles of MHC on Cell Surface

  • MHC Class I:

    • Displays self-peptides to exhibit a ‘healthy’ status

    • Displays foreign peptides to indicate infections and engage CD8+ T cells

  • MHC Class II:

    • Engages TH cells to indicate body infections

    • Tests developing T cells for auto-reactivity, maintaining self-tolerance.

Antigen Processing and Presentation

  • Definitions:

    • Antigen Processing: The process by which peptides are produced from proteins.

    • Antigen Presentation: The process of binding these peptides to MHC molecules that then traffic to the cell surface.

Pathways of Antigen Presentation

Endogenous vs. Exogenous

  • Endogenous Pathway (Class I MHC):

    • Presents cytosolic antigens.

  • Exogenous Pathway (Class II MHC):

    • Presents antigens from outside the cell.

Mechanisms of Antigen Processing

Class I Pathway

  • Peptide Generation:

    • Proteins are tagged for degradation using ubiquitin and processed by proteasomes.

    • An immunoproteasome variant enhances the production of peptide fragments optimal for MHC binding.

    • Nonclassical class I proteins are upregulated in activated APCs.

Transport into the Endoplasmic Reticulum (ER)

  • Role of TAP1 & TAP2:

    • Transporter Associated with Antigen Processing (TAP) proteins move peptide fragments into the rough ER.

    • Efficient transport favors peptides of 8-16 amino acids with hydrophobic C-terminal residues.

MHC Class I Peptide Assembly

  • Role of Chaperones:

    • Chaperones such as Calnexin, ERp57, Calreticulin, and tapasin aid in MHC folding and assembly.

    • β2-microglobulin is incorporated to stabilize MHC Class I.

    • ER aminopeptidase (ERAP1) trims peptides to fit MHC grooves.

Transport of Peptide-MHC to Cell Surface

  • Once peptides are bound to MHC I, they are transported to the cell surface via the secretory pathway, involving the Golgi apparatus and transport vesicles.

Class II Pathway

Steps Involved in the Exogenous Pathway

  • Initiation:

    • Internalization of microbes or macromolecules; resulting in entry into the endocytic pathway.

  • Compartmentalization:

    • Peptide generation occurs within internal compartments (e.g., phagosome, endosome, MIIC).

    • Proteins are degraded into fragments approximately 13-18 amino acids long.

MHC Class II Peptide Assembly and Transport

  • The invariant chain (Ii) associates with MHC Class II during ER translation, blocking premature binding of peptides.

  • Degradation of Ii:

    • Ii is cleaved to CLIP, which is swapped out for peptide fragments by HLA-DM within MIIC.

Comparison of Endogenous and Exogenous Pathways

  • Key Questions:

    • Where does the antigen originate (internal vs. external)?

    • How are proteins degraded into peptides?

    • What compartments are involved in antigen binding to MHC?

    • Which molecules are key in each pathway?

Summary: Class I vs. Class II Pathways

  • Endogenous Pathway:

    • Involves cytotoxic T cells (CD8)

  • Exogenous Pathway:

    • Involves helper T cells (CD4)

Role of MHC in Antigen Presentation

  • MHC Class I: Presents antigen to cytotoxic T cells (Tc); CD8+ T cells kill pathogen-infected cells.

  • MHC Class II: Presents antigen to helper T cells (TH); CD4+ T cells activate macrophages, B cells, and Tc cells.

Cross-Presentation

  • Definition: Presentation of peptides from exogenous antigens on MHC I molecules by redirecting internalized antigens.

Professional Antigen Presenting Cells (APCs)

  • Types:

    • Dendritic Cells (DCs):

    • Constitutively express MHC II and costimulatory molecules, activate naive TH and TC cells.

    • Macrophages:

    • Require activation (e.g., via TLR signaling) before expressing MHC II and costimulatory molecules.

    • B Cells:

    • Constitutive low expression of MHC II, requiring activation before upregulating expression.

Cross-Presentation Mechanism

  • Challenge Identified: Infected cells naturally process peptides for endogenous presentation, but only DCs provide necessary costimulation for CD8+ T cells.

Dendritic Cell Licensing and Cross-Presentation

  • DC Licensing: DCs must be activated by TH cells before they can conduct cross-presentation.

    • Mechanism involves the classical exogenous pathway and subsequent signaling that enhances CTL activation.

Summary of Cross-Presentation on MHC Class I

  • Exogenous antigens can be presented on MHC Class I if they are transferred into the cytosol or imported through a peptide-loaded endosome.

Final Summary of Antigen Presentation Pathways

  • Key Concepts: Most antigens are proteins, and T cells require peptide presentation for activation, with MHC I presenting to CD8 and MHC II presenting to CD4 cells.!