MICR 304 Immunology &

Serology

MICR 304 Immunology &

Serology

Lecture 9 TCR, MHC molecules

Chapter 3.10 – 3.19, 4.9- 4.11, 5.1 – 5.19

Lecture 9 TCR, MHC molecules

Chapter 3.10 – 3.19, 4.9- 4.11, 5.1 – 5.19

Overview of Today’s Lecture

• Generation of T cell receptor (TCR)• MHC molecules• Antigen presentation via MHC

molecules

Key Players in Immunology

Innate Adaptive

Cells PhagocytesEpithelial Cells

NK Cells

Lymphocytes(B-Ly, T-Ly)

Effector molecules

ComplementAntimicrobial (Poly)PeptidesAntimicrobial

Lipids?

Antibodies

T Cell Receptor• 2 chains

– Connected by disulfide bond

– Variable region– Constant region– Short cytoplasmic

tail

• Mostly and chain

• Some specialized T-cells have and chain ( T cells)

T-Cell Receptor Belongs to the Immunoglobulin Super

Family

Gene Segments Coding for the T-Cell Receptor

• Variable region of -chain is composed of V and J gene segments

• Variable region of -chain is composed of V, D and J gene segments

Generation of the TCR by Gene Rearrangement and

Recombination

No secondary modification of TCRs

Diversity of the Lymphocyte Antigen Receptors

P- and N- nucleotides: nucleotides added during initial gene rearrangement and recombination

Unique Properties of TCR Compared to BCR

• Only one antigen binding site• Never secreted• Recognize processed antigen

presented through specialized molecules

TCR Recognizes Antigen Presented by MHC Molecules • MHC: major

histocompatibility complex• First identified in

transplantation immunology • T cells recognize antigen

bound to an MHC molecule • Two types of MHC molecules

– MHC I: presents endogenous peptides

• Virus encoded• Produced by intracellularly

replicating microorganisms• Tumor antigens

– MHC II: presents exogenous peptides

• Uptake through phagocytosis and degradation in phagolysosome

MHC I CTL

MHC II TH

Antigen Recognition through TCR Requires Additional

Molecules• CD3: signal transduction• CD4: Interaction with

MHC II• CD8: Interaction with

MHC ITH CTL

Any nucleated cellAg presenting cell

Cytokines Cytotoxic granules

Contrast TH Cells and CTL

TH CTLCD on surface

CD4 CD8

MHC Interaction

MHC II MHC I

Target cells APC (macrophages, DC, B cells, others)

Any nucleated cell

Response upon activation

Cytokine release Cytotoxic granule release (and some cytokines)

T cells are Distinct

• Minority of T cell population• Bind heat shock proteins and

nonpeptide ligands– Mycobacterial lipid antigen– Phosphorylated ligands

• Not restricted by classical MHC I or MHC II molecules

• May bind to free antigen

Expression of MHC Molecules Differs Between

Tissues• MHC I positive: any

nucleated Cell• MHC II positive: only

antigen presenting cells (APC)– IFN can MHC II in other

cells • APC: take up antigen,

degrade it, load it onto MHC II and present it at their cell surface– Human activated T cells– Microglia in brain

Structure of MHC Molecules

• Exogenous peptides are bound to MHC II along the groove

• 13 - 17 aa

• Endogenous peptides are bound to MHC I by their ends– Ionic interaction

• 8 – 10 aa

MHC I

MHC II

Intracellular Compartment

Exogenous peptides

Endogenous compartment

Subcellular Location of Pathogens and their Products

Endogenous Ag Exogenous Ag

Engage CTL Engage TH cells

Key Molecules in Antigen Presentation

• Proteasomes• TAP1, 2 (Transporters

associated with antigen processing)

• CD8

• Lysosomal proteases• CLIP (class II associated

invariant chain peptide)• B7• CD4• CD28

MHC I

MHC II

On target cell

On CTL

On APC

On TH

Loading of Endogenous Peptides onto MHC I (1)

• Chaperones guide in ER nascent MHC I to TAP

• Endogenous proteins are degraded in proteasome and enter ER through TAP

• Peptide loading occurs in the ER• If peptides are too long they can be trimmed

the endoplasmic reticulum aminopeptidase associated with antigen processing (ERAAP)

• MHC I with peptide loaded is sent to cell surface

Loading of Endogenous Peptides onto MHC I (2)

Viral Strategies to Interrupt Presentation of Viral Peptides• Blocking entry of viral peptides

into ER• Retention of MHC I in ER• Degradation of MHC I via transport

of MHC I into cytosol• Blocking access of CTLs to surface

expressed peptide loaded MHC I

Active Learning Exercise:

By which mechanisms could viruses interfere with the presentation of viral peptides on MHC I at the cell surface?

Loading of Exogenous Peptides onto MHC II

Loading of Exogenous Peptides onto MHC II (1)

• MHC II leaves ER with CLIP– CLIP

• Class II associated invariant-chain peptide• Binds to peptide groove• Prevents premature peptide loading

• MHC II vesicle fuses with phagosome containng degraded exogenous peptides

• HLA-DM removes CLIP from MHC II peptide groove and exogenous degraded peptide can bind– HLA-DM is MHC II like

Loading of Exogenous Peptides onto MHC II (2)

Limitations in MHC Binding Pose a Problem

• How can so many different pathogen derived peptides be presented?

•Introduce variability in MHC molecule•MHC is polymorphic

•MHC is polygenic

Polymorphism and Polygeny Increase

Variability • Polymorphism– Numerous variants (alleles) for each gene– MHC genes are the most polymorph genes known

• Polygeny– Several different genes for MHC I and MHC II– A set of genes with a broader range of peptide binding

is expressed

Genes Coding for MHC Molecules

• 3 genes and gene products for MHC I– A ()– B ()– C ()– 2 microglobulin is

monomorphic• 3 genes and 4 gene

products for MHC II– DR (, 1, 2)– DP (,)– DQ (,)

• Over 1000 alleles• Alleles are co-

dominant expressed

Polygeny Polymorphism

Polymorphism of MHC Genes

… a growing list! Nu

mb

er

of

Diff

ere

nt

Alle

les

Allelic Variation Occurs at Specific Sites with in the MHC

Molecules

The Expression of MHC Alleles is Co-Dominant

Intra- and Interpersonal Variability of MHC

Molecules• Within a person multiple MHC molecules

are expressed– 3 MHC I genes x 2 (father, mother) = 6

MHC I– 4 sets of MHC II genes x 2 (father, mother)

= 8 MHC II

• Cells within a person are uniform• Cells from another persons carry

different sets of MHC molecules!

T Cell Recognition of Antigens isMHC Restricted

MHC molecules participate in antigen recognition.

Superantigens

• Antigens that are not processed

• Crosslink TCR with MHC• Can simultaneously

stimulate 2 - 20% of all T cells.

Non-Classical MHC Genes• Resemble MHC class I genes in structure• Many associate with 2microglobulin• Also called MHC Ib• Comparatively little polymorphism• Some bind to activating NK cell receptors (NKG2D)

– Example: MIC-A– Induced in response to cellular stress– Trigger cytotoxicity

• Some bind to NK inhibitory receptors (NKG2A) – Example: HLA E– Inhibit cytotoxicity– Found on fetus derived placental cells

• Some present lipid antigen to T cells– Example CD1

Refresher: NK Cell Mediated Killing

Today’s Take Home Message

• The TCR consists of two chains, and , and is similar to the arm of an antibody molecule with the TCR -chain representing the light chain and thechain the heavy chain.

• T cell recognize digested peptide presented through MHC molecules.

• T helper cells recognize peptide on MHC II and utilize CD4 to ensure proper binding to MHC II.

• CTL recognize peptide on MHC I and utilize CD8 to ensure proper binding to MHC I.

• MHC are polymorphic and polygenic.

• Non-classical MHC I molecules (MHC Ib) interact with inhibitory and activating NK cell receptors.