Immunology 6: T Lymphocytes and Antigen Recognition

Question 1

Describe T Cell Receptor (TCR)

Answer 1

Related to the structure of antibodies

The variable region interacts with the antigen

Very short cytoplasmic tail

Has alpha and beta components

A small subset uses gamma and delta chains

Diversity in the variable region results by the combination of gene segments (like VDJ recombination)

TCR is a member of the immunoglobulin superfamily

Question 2

What is the importance of the CD3 polypeptide

Answer 2

CD3 polypeptides are a constant part of the TCR

They are important in the delivery of the signal to the T lymphocyte once the antigen has been recognised.

The tails have motifs containing tyrosine residues

Question 3

What happens when a tcr meets its antigen

Answer 3

PHOSPHORYLATION OF TYROSINE in the motifs occur

This triggers several other chemical cascades

ITAM = Immunoreceptor Tyrosine-based Activation Motif

Question 4

TWO MAJOR POPULATIONS OF T cells:

Answer 4

CD4 - MHC Class II

CD8 - MHC Class I

Question 5

What is the role of CD4 cells

Answer 5

T helper cells

Secretes cytokines

Recruit effector cells - activate macrophages

Help and activate CTL and B cell responses

Question 6

What is the role of CD8 cells

Answer 6

Cytotoxic T Lymphocytes

Kill target cells

Induce apoptosis in target cells

Question 7

Describe T cell development in the thymus

Answer 7

(In the cortex)
When the precursors arrive at the thymus, they have NO TCR, CD4 or CD8 - there are no co-receptors or antigen specific receptors

Rearrangement of the gene segments takes place to form
preTCR beta chain

Then CD4 and CD8 are expressed along with a full TCR

(In the medulla)
There is a selection process to see which kind of MHC molecule the cell can recognise

Depending on which type of MHC they recognise, they will either become CD4+ or CD8+

Question 8

How are the different TCR receptor alpha and beta chains formed

Answer 8

Similar to how antibody diversity is generated but with different gene segments

Beta chain is rearranged FIRST

Beta chain has VDJ

Alpha chain is rearranged SECOND

Alpha chain has VJ

Diversity is achieved by randomly selecting from the gene segments available

Question 9

Define Major Histocompatibility Complex

Answer 9

a group of tightly linked genes that are important in specific immune responses.

Question 10

MHC Class I Structure

Answer 10

Two Separate Chains:

Alpha Chain - Heavy

b2-microglobulin - Light

Alpha Chain = POLYMORPHIC

B2-microglobulin = SAME IN EVERYONE

The light chain (B2-microglobulin) associates NON-COVALENTLY with the alpha chain

Both domains are immunoglobulin like domains so MHC are part of the immunoglobulin superfamily

Peptides bind between the alpha-1 and alpha-2 domains

Question 11

MHC Class II Structure

Answer 11

Similar in structure of MHC Class I

DIFFERENCE: There are two polypeptides of equal size which are BOTH transmembrane

There is an alpha chain and a beta chain which are equal in size

Peptide binds between alpha-1 and beta-1

Question 12

Where do CD4 and CD8 bind

Answer 12

CD4 and CD8 ARE CO-RECEPTORS WHICH BIND TO THE SIDE OF THE MHC MOLECULE - THEY DO NOT BIND TO THE ANTIGEN PRESENTED BY THE MHC, TCR DOES THAT!

Question 13

Which MHC present the shorter peptide

Answer 13

MHC Class I presents peptides that are 8-10 amino acids long - SHORTER PEPTIDES

MHC Class II presents longer peptides (13+ amino acids) - LONGER PEPTIDES

Ends of the peptide often sticks out of the peptide binding site on the MHC.

Question 14

How are polypeptides binded to MHC

Answer 14

They do this by having certain positions on the MHC that are relatively CONSERVED that anchor the peptide into BINDING POCKETS in the MHC.

There are binding pockets within the MHC molecules - within the peptide there will be certain positions that are always more or less exactly the same amino acid.

This is known as a BINDING MOTIF

This means that MHC presents a subset of peptides which have some things in common where characteristics are conserved.

Question 15

What is the MHC in humans called?

Answer 15

The HLA (Human Leukocyte Antigen) region

Question 16

Describe the Human Leukocyte Antigen

Answer 16

The polypeptides that make up the MHC molecules are encoded within the HLA region

Three types of Class I = A, B and C

Three types of Class II = DP, DQ and DR

In class I it is only the heavy chain that is encoded within HLA - B2-microglobulin is encoded on a different chromosome

We are diploid so we have two sets like this meaning that we can have up to SIX different class I and class II molecules

Question 17

MHC Gene Expression

Answer 17

MHC is polygenic - there are several class I and class II loci

It is CODOMINANT - maternal and paternal genes are both expressed

MHC Class I - nearly ALL CELLS - expression varies during infection or by cytokines

MHC Class II - only on PROFESSIONAL APCs - regulated by cytokines

Question 18

Are MHC same in everyone

Answer 18

no

MHC IS HIGHLY POLYMORPHIC

Question 19

What is a MHC Haplotype

Answer 19

group of MHC alleles linked together on a single chromosome

Question 20

Define Exogenous and what MHC class are they related too

Answer 20

captured from outside e.g. via phagocytosis

Exogenous antigens are presented via MHC Class II to CD4 T cells

Question 21

Define Endogenous and what MHC class are they related too

Answer 21

synthesised within cells e.g. virus

Endogenous antigens are presented via MHC Class I to CD8 T cells

Question 22

Name 3 Antigen presenting cells and their locations

Answer 22

Dendritic Cells
Widely spread
e.g. skin & mucosal tissue

B cells
Lymphoid Tissue

Activated Macrophages Lymphoid Tissue

Question 23

Antigen presentation via MHC Class I

Answer 23

There are viral proteins in the cytoplasm

Viral proteins are processed - proteasome

The peptides then move into the ER via TAP (transporter associated with antigen processing)

Newly synthesised MHC Class I moves into the ER (it has a signal sequence)

It associates with chaperone proteins which aids its folding

The class I heavy chain binds to the peptide and b2-microglobulin

Once all three are correctly folded, it can go via the golgi to the cell surface for possible recognition by CD8 positive T lymphocytes

Question 24

Antigen presentation via MHC Class II (exogenous)

Answer 24

Proteins are endocytosed and processed into peptides in endocytic vesicles

The class II molecules get into the ER (as they have signal sequences)

Once in the ER it associates with INVARIANT CHAIN

Invariant Chain - stops peptides that need to be loaded onto MHC Class I from being loaded onto Class II. It also has a targeting signal sequence so the molecules go to the endocytic pathway via golgi

Once they enter the endocytic pathway, the invariant chain is digested away

You end up with a small peptide fragment derived from the invariant chain bound to the MHC Class II known as the CLIP peptide (Class II Associated Invariant Chain Peptide)

Last Step - swapping the CLIP peptide for the antigenic peptide

The antigenic peptide is then loaded onto MHC Class II and moves to the cell surface for recognition by CD4 T lymphocytes