TCR, MHC and antibodies

Question 1

Give an overview of T-cells?

Answer 1

An antigen is presented as an epitope by an MHC on a APC and recognised by a TCR
After clonal expansion we produce a large population of effector T-cells and memory T-cells
There are two T-cell sub populations: CD4 T-cells and CD8 T-cells
CD = cluster of differentiation

Question 2

What is the structure of a T-cell receptor (TCR)?

Answer 2

2 chains: 1 alpha 45 KD and 1 beta 40 KD connected by a disulphide bond
It has 4 domains (2 in each chain), 2 of which are variable domains - these determine the specificity of the T-cell for an antigen
The two chains are also connected at the top where there is an anitgen recognition site

Question 3

Describe T-cell epitopes?

Answer 3

Short contiguous peptides, typically 8 to 12 amino acids in length, although can be longer for MHC class II molecules
Can be from anywhere in the folded structure of a protein, i.e. can be either surface exposed or buried within the folded structure of the protein

Question 4

What are the two MHCs and what are they linked to?

Answer 4

MHC class I  recognised by CD8 + T cells 
MHC class II recognised by CD4+ T cells

Question 5

Describe MHC class I’s, involved in antigen presentation?

Answer 5

Important in immune response to viruses and to cancer
They are expressed on the cell surface by all nucleated cells
They present intracellular (endogenous) antigens from within the antigen presenting cell eg viral proteins and tumour antigens

Question 6

What is the pathway of MHC class I?

Answer 6

Virus
Synthesis of viral proteins
Viral proteins hydrolysed by proteasome
Epitopes are moved into the ER to bind with a MHC
This complex is moved to the Golgi
Now the viral presentation of viral proteins

Question 7

Describe MHC class II’s, involved in antigen presentation?

Answer 7

MHC class II molecules are expressed on the cell surface of ‘professional’ antigen presenting cells: B-cells, dendritic cells and macrophages
MHC class II molecules present extracellular (exogenous antigens) that are taken up by endocytosis from outside of the cell

Question 8

What is the pathway of MHC class II?

Answer 8

Antigen is taken in to a cell by endocytosis
Antigen is proteolysed by endosomal proteins in an endosome
Meanwhile a MHC II + invariant chain moves from the ER to the Golgi to the Endosome
Now invariant chain also undergoes proteolysis
This whole complex leaves the cell via exocytosis and present the antigen peptide

Question 9

What is the structure of the MHC class I molecule?

Answer 9

Large heavy alpha chain with 3 domains (2 of these form the peptide binding site)
1 beta2-microglobulin domain

Question 10

What is the structure of the MHC class II molecule?

Answer 10

1 alpha chain - 2 domains
1 beta chain - 2 domains

1 of each domain forms the peptide binding site

Question 11

What are the genetics of the MHC complex?

Answer 11

The MHC molecules are polygenic. There are more than one gene for the MHC class I and MHC class II molecules
The genes are present on human chromosome 6, in a region enriched in immune genes
Each MHC molecule gene has multiple alleles (versions)
Alleles expressed co-dominantly (2 alleles for each protein)
Polymorphic residues are concentrated within the peptide binding grove of MHC class I molecules

Question 12

What property do MHC complexes have? why is this useful?

Answer 12

They are polygenic and polymorphic
This is useful because having many combinations allows us to be able to present an increased number of different peptides to T-cells
It is therefore difficult for pathogens to change their protein sequences to prevent the presentation of their antigens

Question 13

What is the role of MHCs in transplants?

Answer 13

Mismatched MHC molecules make tissues and organs histoincompatible
The successful transplantation of organs or bone marrow requires that MHC molecules are closely matched between donor and recipient
Mismatched MHC transplants are more likely to be rejected
Ideal donors for transplants are identical twins (100% matched MHC)

Question 14

What is another name for an antibody?

Answer 14

Immunoglobulin

Question 15

What is an immunoglobulin’s structure?

Answer 15

2 heavy chains and 2 light chains
2 identical binding sites so they can interact with an epitope due to complementary surface
Fragment crystallisable region (Fc) - the tail of the antibody that interacts with cell surface receptors

Question 16

What is the importance of an immunoglobulin?

Answer 16

Used in adaptive immunity
Present in extracellular fluid: blood, tissue fluid and mucous secretions
They bind to antigens e.g. Toxin/pathogen

Question 17

What is the function of an immunoglobulin?

Answer 17

They can combat pathogens by:
Neutralisation - bind to antigen and block the antigen (of a toxin/virus/bacteria) interacting with other molecules e.g. Targets and host cells
They mask the surface of the antigen

Opsonisation - they can be recognised
Fc receptors bind to Fc region of immunoglobulin-antigen complexes
Phagocytosis of immunoglobulin-antigen complexes leads to the degradation of the antigen

Complement activation
Complement mediated neutralisation/lysis and phagocytosis via complement receptors

Question 18

What is a disease linked to immunoglobulin’s

Answer 18

Deficiency in b-lymphocytes and antibody production = X-linked agammaglobulinemia (XLA)
They have increased susceptibility to pyogenic bacteria (production of pus)

Question 19

Describe B-lymphocytes?

Answer 19

B-lymphocytes express on their cell surface a membrane bound immunoglobulin = B cell receptor (BCR) for an antigen

Recognition and capture of antigen by the BCR drives the proliferation of that B-lymphocyte and the generation of:
long lived memory cells: specific for the antigen
short-lived immunoglobulin secreting plasma cells that secrete large quantities of immunoglobulin specific for the antigen (effector cell)

Question 20

Describe plasma cells?

Answer 20

Found in secondary lymphoid tissues and also migrate back to the bone marrow
Short lived terminally differentiated B-cells. Live only 24-48 hours
They secrete large amounts of antibodies in response to an antigen
Immunoglobulins enter the blood through the lymphoid tissue and circulate through the vascular system
They have large amounts of RER - antibody synthesis

Question 21

Describe memory cells?

Answer 21

They express membrane immunoglobulin, but do not secrete significant quantities of immunoglobulins
If antigen is encountered again, memory cells are stimulated to divide generating additional memory cells and plasma cells
The second response is faster and greater in amplitude than the initial response

Question 22

Describe breifly the journey of a B-lymphocyte?

Answer 22

B-lymphocytes are generated in bone marrow (primary lymphoid tissue)
Once differentiated they exit the bone marrow
They migrate to the secondary lymphoid tissues (spleen, MALT and lymph nodes)
They die within 3 weeks if they don’t detect an antigen
If they do detect an antigen they undergo antigen dependent differentiation = memory cells and plasma cells

Question 23

How do antigens get to the B-lymphocytes?

Answer 23

Antigen get to the lymph nodes via lymphatic vessels (afferent), antigens get to the spleen via the blood stream
The sites where B-lymphocytes proliferate are germinal centres
Plasma cells are generated and move to the medullary cords or to the bone marrow
Once the antigen is cleared the germinal centres shrink