B and T cells and MHC

Question 1

State the main differences between B and T cells.

Answer 1

B CELLS:

• Antibody secreting cells
• Come from bone marrow straight into circulation and then into lymph organs

T CELLS:

• Variety of other functions in immune response
• Come from bone marrow into thymus as T cell precursor cells where spend 7-21 days undergoing differentiation and proliferation into a mature (but antigen naive) phenotype, before going to circulation and lymph organs (same locations as B cells)

Question 2

Do all T cell precursor cells go on to go to circulation as mature T cells ? Explain how, or how not.

Answer 2

No, only 2-4% of T cell precursor cells leave thymus as mature T cells to populate lymph nodes etc. What happens to the rest? Thymus maintains same size but over 95% of thymocytes die in thymus.
Due to EDUCATING OF T CELLS

Question 3

Describe the process of educating T cells.

Answer 3

• (Immature) Small double negative thymocytes are the earliest developing thymocytes, lacking the expression of the co-receptors CD4 and CD8. They then differentiate into (Immature) Small double positive thymocytes (CD4 and CD8), which initially express low levels of the receptor they use to recognise antigen, the TcR (T-cell receptor)
• Most of these TcRs won’t recognise your own Major Histocompatibility Complex (MHC) molecules so the T cells die because of a lack of ‘positive selection’.
• Those cells that do see your own MHC go on to mature and express high levels of TcR. They then lose either CD4 or CD8 to become single positive cells.
• During this latter stage the T cells also undergo ‘negative selection’, to eliminate T cells that see your own MHC with high affinity, ie which could become autoreactive T cells.

Question 4

Describe the structure of the T cell Receptor.

Answer 4

2 chains (Alpha and Beta), each with a variable region (includes antigen binding site)  and a constant region (towards the membrane) 
Also a Transmembrane Region and Cytoplasmic Tail

Question 5

Where in the T cell is the T cell receptor located ?

Answer 5

T cell receptor always embedded in membrane of T cell

Question 6

How are TcRs and antibodies related ?

Answer 6

Evolutionary related. Both are members of the ‘Immunoglobulin Superfamily’ .

Question 7

Why and how is T cell receptor diversity generated ?

Answer 7

To generate antigen-binding diversity. Each T cell bears a single specificity and a single allele of TCR.

Through chromosomal rearrangement and gene splicing

Question 8

How are TcRs and MHC linked ?

Answer 8

TcR only ever recognises an antigen when it is bound by an MHC molecule. Hence, TcR recognition of antigen is ‘MHC- restricted’ .

Said antigen is taken from cell by MHC, because MHC molecules are peptide binding molecules (e.g. viral protein)
Proteins are degraded inside the cell (have a certain life span)
MHC therefore take protein fragment (the antigen) inside the cell and binds onto it and ‘presents’ it by putting it on GROOVE on cell surface
Since the antigen is not self, the T cell floating around will detect it (through binding of TCR on T cell with antigen on MHC molecule), and become activated

Question 9

Describe the types of MHC molecules.

Answer 9

MHC Class 1

• Two chains, a heavy alpha chain (divided into alpha1, 2, and 3), and a small B2- microglobulin (peptide-binding groove made up by alpha 1 and alpha 2 domains of alpha chain)
• Upper surface forms a groove into which small 8-10 amino acid peptides sit.
• Expressed on almost every cell in your body, though at low levels in some (eg CNS)
• MHC class I is recognised by CD8 T cells (CD8 receptor binds to back end of MHC in addition to THR receptor binding to antigen on MHC)
• MHC class I picks up peptides mostly derived from the internal contents of your cells, e.g. cytoplasm and nucleus (meets peptides in the endoplasmic reticulum (ER) after antigen has been processed to peptides and transported to ER)

MHC Class 2

• Two chains, alpha (alpha 1 and 2 domains) and beta (beta 1 and 2 domains), both membrane bound (peptide-binding groove made up by alpha 1 and beta 1 domains)
• Upper surface forms groove into which longer peptides, over 20 amino acids sits.
• Expression more limited to specialised antigen presenting cells and immune cells, e.g. macrophages, dendritic cells, B and T cells.
• MHC class II is seen by CD4 T cells (CD4 receptor binds to back end of MHC in addition to THR receptor binding to antigen on MHC)
• MHC class II picks up peptides derived from external sources, ie outside your cells (meet peptides in endosomes after antigen has been processed to peptides)

Question 10

Describe the main features HLA.

Answer 10

• Human leukocyte antigen is a gene complex encoding the MHC proteins in humans
• Present on chromosome 6
• Inherited one set from mom and one set from dad
• Class I HLA genes (A, B, and C), correspond to class I MHCs
• Class II HLA genes (DP, DM, DOA, DOB, DQ, and DR) correspond to class II MHCs
• MHC molecules highly polymorphic so virtually everyone (except twins) have different MHC molecules, presenting different peptides (so all presenting different parts of pathogen to immune system, which means different responses to pathogen, evolutionarily favorable)

Question 11

Outline the relevance of HLA and MHC to tissue transplantations.

Answer 11

The major factor in graft rejection is MHC disparity. Why? Your own T cells are educated to see your own MHC molecules. Anyone else’s are similar, but just different enough to cause a response. Thus MHC matching is crucial to improve graft survival. Even if a full match is obtained, you have enough different peptides (called minor transplantation antigens) to trigger a slow graft rejection, so immunosuppression still required.

T cells would see the peptides presented by the MHC as foreign, since we all have different MHCs producing different peptides (so MHC from donor will present a peptide our own body views as foreign). As a result T cells would become activated and trigger graft rejection

Question 12

What are polymorphisms in MHCs due to ?

Answer 12

Polymorphisms are located in the peptide-binding groove (AA changes in peptide binding groove)

Question 13

List examples of diseases with an HLA association.

Answer 13

1. AUTOIMMUNITY
   - Ankylosing spondylitis: HLA-B27
   - Multiple sclerosis: HLA-DR2
   - Type I IDDM: HLA-DR3/DR4
   - Rheumatoid arthritis: HLA-DR4
   - Transplantation: T cells are educated to see your own MHC molecules. Anyone else’s are similar, but just different enough to cause a response. Thus MHC matching is crucial to improve graft survival. Even if a full match is obtained, you have enough different peptides (called minor transplantation antigens) to trigger a slow graft rejection, so immunosuppression still required
2. CANCER (A multitude of tumour lines from the different stages of B and T cell development)
   -Acute lymphoblastic leukemia
   -Thymoma:thymicstromalorepithelialcell, cytokeratin high
   - Acute lymphoblastic leukemia (T-ALL): thymocyte, CD1
   - Adult T cell leukemia, Chronic lymphocytic leukemia: T cell CD3, CD4, CD8
   • Hodgkin’s disease: B cell lineage, large (Reed- Sternberg) cells
3. SUPERANTIGENS (some bacteria and viruses produce proteins that interfere with the interaction of TcR and MHC, stimulating large numbers of T cells)
   - Toxic Shock Syndrome: Staphylococcal enterotoxin (SEB) and TSST-1
4. DEVELOPMENTAL PROBLEMS
   - DiGeorge’s syndrome: failure to develop thymic epithelia, few T cells are produced.
5. LOSING SUB-POPULATIONS OF CELLS
   - Severe combined immunodeficiency (SCID): loss of the T cell compartment leads to loss of ability to produce cell mediated and antibody responses.
   - Bare lymphocyte syndrome: can affect class II -and class I. Class II deficient patients still produce CD8 T cells, but still have SCID because CD4 cells control immune responses. Class I deficient patients have few CD8 T cells but manage to have reasonable immune responses against most pathogens.