MHC and antigen processing

Course 6 Lucian P. Jiga, MD PhD

Meet the players

Meet the players

APCs

Meet the players

APCs T-cells

Meet the players

APCs Immune synapse T-cells

Meet the players

APCs Immune synapse

Antigen

T-cells

APCs

T-cells

Immune synapse

Text

Suzuki et al, Nature Immunology, 2008

Immune synapse Signal 1 - antigen recognition

Text

Suzuki et al, Nature Immunology, 2008

Immune synapse Signal 1 - antigen recognition Signal II/III - Costimulation

Text

Suzuki et al, Nature Immunology, 2008

HOW do Antigens meet APCs?

Abbas, Cellular & Molecular Immonology, 2006

WHERE does Ag-recognition takes place?

http://labs.idi.harvard.edu/vonandrian/Pages/nrivideospage_new.html http://academic.kellogg.edu/herbrandsonc/bio201_mckinley/Lymphatic%20System.htm

HOW does Ag-recognition takes place?

Abbas, Cellular & Molecular Immonology, 2006

Property of Ronald M. Germain - Laboratory of Systems Biology, NIAID, USA

HOW does Ag-recognition takes place?

Abbas, Cellular & Molecular Immonology, 2006

Property of Ronald M. Germain - Laboratory of Systems Biology, NIAID, USA

HOW is Antigen presented ?

Abbas, Cellular & Molecular Immonology, 2006

Discovery of MHC ?

Sir Peter Medawar 20y Baruj Benacerraf

Ir (immune response) genes II MHC genes

Abbas, Cellular & Molecular Immonology, 2006

Discovery of MHC ?
Alloantisera

Jean Dausset Blood transfusion Organ Tx

Alloantibodies Alloantigens

Human Leukocyte Antigens

Abbas, Cellular & Molecular Immonology, 2006

WHAT is MHC ? MHC = major hystocompatibility complex MHC = HLA (human leukocyte antigens) cytosolic antigen
A, B, C

MHC class I MHC class II

DP, DQ, DR

CD8 T cells CD4 T cells extracellular antigen

Abbas, Cellular & Molecular Immonology, 2006

MHC class I

heterodimer: - alpha chain - (beta)2 microglobulin - bound antigen

Abbas, Cellular & Molecular Immonology, 2006

MHC class II

heterotrimer: - alpha chain - beta chain - bound antigen

Abbas, Cellular & Molecular Immonology, 2006

Peptide - MHC interactions

1. Each MHC (I or II) can bind only 1 peptide at a time 2. Each MHC (I or II) can bind many different peptides 3. MHC-binding is dictated by peptide size - MHC-I = 8 - 11 residues - MHC-II = 10 - 30 residues 4. Antigenic peptide - MHC molecules = saturable interaction, slow off-rate 5. MHC molecules do not discriminate between self and non-self antigens

MHC expression

1. MHC class I molecules expressed on all nucleated cells 2. MHC class II molecules expressed ONLY on dendritic cells, B cells, MCF 3. MHC expression increased by cytokines (IFNg) innate/adaptive immunity 4. Rate of transcription is determinant for the level of MHC expression

MHC-I vs. MHC-II ?

Abbas, Cellular & Molecular Immonology, 2006

MHC-II antigen processing/presentation

Abbas, Cellular & Molecular Immonology, 2006

MHC-II antigen processing/presentation

Abbas, Cellular & Molecular Immonology, 2006

MHC-II antigen processing/presentation

Abbas, Cellular & Molecular Immonology, 2006

MHC-I antigen processing/presentation

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

1. T-cell surveillance

- T-cell continuously sample Ag in the context of MHC

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

1. T-cell surveillance

- T-cell continuously sample Ag in the context of MHC - Majority of Ag are self = NO T-cell response

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

1. T-cell surveillance

- T-cell continuously sample Ag in the context of MHC - Majority of Ag are self = NO T-cell response

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

1. T-cell surveillance

- T-cell continuously sample Ag in the context of MHC - Majority of Ag are self = NO T-cell response

Thymus deletion

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

1. T-cell surveillance

- T-cell continuously sample Ag in the context of MHC - Majority of Ag are self = NO T-cell response

Thymus deletion

Anergy

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

1. T-cell surveillance

- T-cell continuously sample Ag in the context of MHC - Majority of Ag are self = NO T-cell response

Thymus deletion

Anergy

- Foreign Ag (microbial origin, Tpl) non-self = Clonal T cell expansion

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

1. T-cell surveillance

- T-cell continuously sample Ag in the context of MHC - Majority of Ag are self = NO T-cell response

Thymus deletion

Anergy

- Foreign Ag (microbial origin, Tpl) non-self = Clonal T cell expansion - MHC molecules continuously pick-up Ag: extracellular and cytosol located - Only traces of Ag can be identied by T cells as non-self - sensitivity

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

1. T-cell surveillance

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

2. Ag origin and T cell activation

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

2. Ag origin and T cell activation

Extracellular

MHC-II restricted CD4-helper Tcell activation

activates B cells Th1 cytokines activates MFG

Abbas, Cellular & Molecular Immonology, 2006

Signicance of MHC-associated Ag presentation

2. Ag origin and T cell activation

Extracellular

Cytosolic

MHC-II restricted CD4-helper Tcell activation

MHC-I restricted CD8-cytotoxic Tcell activation

activates B cells Th1 cytokines activates MFG

Abbas, Cellular & Molecular Immonology, 2006

Direct killing of Ag-producing cells

Summary
- Tcells only recognize peptides displayed on self-MHC on APCs - APCs internalize, process & present Ag on MHC-II for CD4 helper Tcells - All nucleated cells - cytosolic peptides on MHC-I to CD8 cytotoxic Tcells - Ag procesing = conversion of proteins into MHC-associated peptides

Abbas, Cellular & Molecular Immonology, 2006

Summary
MHC - II antigen processing
Internalization - endosome cleavage/enzymes

Cell Surface

peptide MIIC (new MHC) CLIP

ER - production of chaperons + (new MHC) CLIP

Abbas, Cellular & Molecular Immonology, 2006

Summary
MHC - II antigen processing
Internalization - endosome cleavage/enzymes

Cell Surface

peptide MIIC (new MHC) CLIP

(new MHC)

ER - production of chaperons + (new MHC) CLIP

Abbas, Cellular & Molecular Immonology, 2006

Summary
MHC - II antigen processing
Internalization - endosome cleavage/enzymes

Cell Surface

peptide MIIC (new MHC) CLIP

(new MHC) CLIP

ER - production of chaperons + (new MHC) CLIP

Abbas, Cellular & Molecular Immonology, 2006

Summary
MHC - II antigen processing
Internalization - endosome cleavage/enzymes

Cell Surface

peptide MIIC (new MHC) CLIP

(new MHC) CLIP enzymes +HLA-DM

ER - production of chaperons + (new MHC) CLIP

Abbas, Cellular & Molecular Immonology, 2006

Summary
MHC - II antigen processing
Internalization - endosome cleavage/enzymes

Cell Surface

peptide MIIC (new MHC) CLIP

(new MHC) enzymes +HLA-DM

ER - production of chaperons + (new MHC) CLIP

Abbas, Cellular & Molecular Immonology, 2006

Summary
MHC - II antigen processing
Internalization - endosome cleavage/enzymes

Cell Surface

peptide MIIC (new MHC) CLIP

(new MHC) enzymes +HLA-DM (new MHC-II) + peptide

ER - production of chaperons + (new MHC) CLIP

Abbas, Cellular & Molecular Immonology, 2006

Summary
MHC - II antigen processing
Internalization - endosome cleavage/enzymes

Cell Surface

(new MHC-II) + peptide

peptide MIIC (new MHC) CLIP

(new MHC) enzymes +HLA-DM

ER - production of chaperons + (new MHC) CLIP

Abbas, Cellular & Molecular Immonology, 2006

Summary
MHC - I antigen processing

Abbas, Cellular & Molecular Immonology, 2006