Antigen presentation to T lymphocytes

Chapter 5

Objectives

• Explain and illustrate the mechanisms of antigen processing for presentation on – MHC I– MHC II

• Describe how polygeny and polymorphism contribute to variation in MHC in a population

Antigen processing

• Antigen processing: degradation of proteins into peptides that can be presented on MHC I or MHC II

– MHC I presents peptides derived from cytoplasmic antigens

– MHC II presents peptides derived from extracellular or intravesicular antigens

Antigens are derived from cytosolic or vesicular

compartments

Antigen processing for MHC I

• Cytoplasmic proteins are degraded by the proteasome

Antigen processing for MHC I

• The proteasome exists in two forms:– Constitutive– Immunoproteasome

(interferon-inducible)

Antigen processing for MHC I

• MHC I is a transmembrane protein made in the ER

• Cytoplasm-derived peptides must be transported into the ER to bind MHC I

Antigen processing for MHC I

• MHC I antigen processing animation

Antigens are derived from cytosolic or vesicular

compartments

Antigen processing for MHC II

•Extracellular proteins are processed in endosomes by hydrolytic enzymes

MHC II expression pattern in cells

Wubboltz et al, J Cell Biol 135:611-622, 1996

Lysosome markerGFP-tagged MHCII

Both signals

Antigen processing for MHC II

• The invariant chain (Ii) blocks the MHC II peptide-binding cleft while it is in the ER

• Acid proteases cleave Ii but leave a fragment (CLIP) in the peptide-binding groove

Antigen processing for MHC II

• MHC II antigen processing animation

GFP-tagged Mycobacterium tuberculosisAcidotropic dye (fluoresces in acidic vesicles)

Guitierrez et al, Cell 119:753-796, 2004Rap = rapamycin (antibiotic)

Humans have many variants of MHC I and II

• Human MHC proteins are called Human Leukocyte Antigen (HLA) class I and class II

• HLA molecules are polygenic and highly polymorphic

• Each HLA I or HLA II has a different range of peptide binding specificities

Organization of HLA genes

Polymorphism of HLA genes

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f allele

s (

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Polygeny and polymorphism of HLA