Antigen Recognition & Presentation

Describe MHC

• Two Types?

• Differentiate between the two classes:

  • location

  • Antigen presentation

  • Presentation to which cells?

  • Structure

• Describe the MHC genetics

  • Dominance pattern?

  • Inherited as?

  • Describe the genes for the different chains in Class 1 and 2

• Describe MHC I genes

  • What are the two types?

    • describe its morphism

    • Function?

• Describe MHC II genes

  • What are the two types?

    • describe its morphism

    • Function?

• Describe Allelic Variation

  • Location

  • Mech

  • Function

• Define:

  • polymorphism

  • polygeny

• Describe the relationship between Natural Selection and MHC diversity:

MHC

• two types:

  • autologous (Self)

  • allogeneic (Non-self)

    • 1-10% of circulatory T cells in most individuals are alloreactive

• Two Classes: MHC Class I; MHC Class II:

  • Location:

    • Class I: almost all nucleated cells

    • Class II: on professional APCs only

  • Antigen Presentaiton:

    • Class I: from inside the presenting cell

    • Class II: from outside (engulfed)

  • Presenting to which Cells:

    • Class I: CD8 T Cells (killer)

    • Class II: CD4 T Cells (Helper)

  • Structure:

    • Class I: 3 Alpha Chains + 1 β₂‑microglobulin ; “Cup”

    • Class II: 2 alpha + 2 beta; “hotdog”

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MHC Genetics:

• Co-dominant

  • (Genes from both parental chromosomes are expressed at the same time in the same cell)

• Inherited as HAPLOTYPES

  • definition: cluster of alleles on one chromosome that are inherited together.

    • Class II region, Class I region, Class III region (no MHC genes here)

• alpha vs beta chain genes:

  • Class I:

    • α-chain: six genes

    • β2-macroglobulin: one gene that pairs w/ all α-chain genes

  • Class II:

    • α-chain: five genes

    • β-chain: multiple genes that pair with a specific α-chain gene

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MHC I genes

• HLA-A, HLA-B, HLA-C

  • highly polymorphic (many alleles)

  • interact w/ CD8+ T cells

• HLA-E, HLA-F, HLA-G

  • oligomorphic (a few alleles)

  • have roles associated with NK cells

• These codes for alpha-chains; pairs up w/ B2 microglubulin

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MHC II genes in humans

• HLA-DP, HLA-DQ, HLA-DR

  • highly polymorphic

  • interact w/ CD4+ T cells

  • HLA-DR = Diverse in Gene

    • Everyone has DRB1; Some people also have DRB3 OR DRB4 OR DRB5

• HLA-DM, HLA-DO:

  • oligomorphic,

  • control how peptides are loaded into the other MHC II molecules

• These represent a few α-chain genes and many β-chain genes

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Allelic Variation

• Occurs w/in Peptide Binding Grooves

  • a1 and a2 domains of MHCI

  • b1 domain of the MHCII

• Mech:

  • substitutions of 1-50 amino acids.

• Function:

  • influences the types of peptides each isoform will bind.

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• Definition:

  • Polymorphism:

    • multiple alternative forms of a gene (allele) within the population.

  • Polygeny:

    • multiple similar genes encoding the same thing

• Natural Selection and MHC diversity:

  • Balancing selection:

    • tends to maintain a given polymorphism

  • Directional selection:

    • tends to introduce new haplotypes

Describe Interferon-gamma

• Produced by?

• Function? Mechanism?

IFN-γ

Production:

• by NK cells during innate immune responses

• by T cells during adaptive immune responses

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Function:

• induces the expression of MHCI

  • IFN-γ → Jak-Stat → act. NLRC5 (MHC Class I Transactivator) → controls expression of MHC I genes

• induces the expression of MHCII

  • IFN-γ → signaling → act. CIITA (MHC Class II Transactivator) → controls expression of MHC II genes

1. What is the difference between Antigen Processing versus Presentation

2. What determines which peptides gets presented?

Antigen Processing versus Presentation

• Processing:

  • Internal pathways in cells that prepare and load antigens into MHC molecules

• Presentation:

  • MHC molecules loaded with peptide delivered to the surface and presented to T cells

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Which peptides gets presented?

• Dependent on Affinity to MHC and Abundance (higher = more likely)

Describe the Mechanism for processing for MHC ClassI/II

MHC Class I:

• Endogenous Pathway

  • Misfolded proteins in cytosol → tagged by ubiquinate → proteosome cleaves → remnants peptides transported to ER via TAP → Joins w/ MHC molecules → trafficked to cell surface

    • Prior, MHC is unstable and helped by chaperon proteins; once peptide binds, chaperon leaves

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MHC Class II:

• Exogenous Pathway:

  • Proteins are phagocytosed → Acidification → act. lysosomal enzymes degrading proteins

    • MHC + Ii (invariant chain; chaperon) → leaves ER in vesicle → Ii degraded, turns into CLIP ↗ vesicle fuses

    • HLA-DM dissociates CLIP + facilitates high affinity peptide binding → sent to PM

Describe what happens to MHC Class I @ homesostasis:

@ homeostasis, self-peptides are presented.

• Cells are always presenting antigen via MHC molecules

  • constitutive process.

• When there are no pathogens around, the peptides in the MHC grooves are from self-antigens that are processed in either the endogenous or exogenous pathway.

List the Professional Antigen Presenting Cells:

• Location

• Roles?

Differentiate between Conventional Dendritic Cells (cDCs) and Plasmacytoid Dendritic Cells (pDCs)

• Location

• Function

cDCs vs pDCs:

• Location:

  • cDCs:

    • Cycle between the tissues and the lymph nodes

  • pDCs:

    • Tissue resident

• Functions:

  • cDCs:

    • antigen uptake and presentation

    • generate cytokines → act. T Cells

  • pDCs:

    • produces type 1 interferons

    • can present antigen but not efficienctly

1. Differentiate between immature and mature DCs

   • Phagocytosis ability

   • presentation ability

   • Cytokine secretion

   • what happens when it travels to T cell zone

2. How does Immature → mature

Immature vs mature:

• Phagocytosis:

  • Immature: Great @

  • Mature: Poor @

• Presentation:

  • Immature: Poor @

  • Mature: Great @

• Cytokine Secretion:

  • Immature: Little to no

  • Mature: Massive secretions

• Co-stimulatory molecules

  • Immature: no expression

  • mature: high expression

• Travels to T cell zone

  • Immature: no act.

  • mature: Activates T cells

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Immature → mature:

• via danger signals

  • PAMPs

  • Inflammatory cytokines

  • DAMPs