Lecture 24. Cellular immunity and histocompatibility Flashcards
what does polymorphic mean?
Polymorphism, as related to genomics, refers to the presence of two or more variant forms of a specific DNA sequence that can occur among different individuals or populations.
same gene, different AA sequence
where do T cells develop, mature?
thymus
large before birth, when all the production of lymphocytes happens
and gets smaller after birth
when do T-lymphocytes express both CD4 and CD8 receptors
-when they are in the immature thymocyte stage
how many % of lymphocytes have CD4 and CD8 receptors?
CD4+ ~80%
CD8 + ~20%
Treg cells
switch off the immune response
Th1 cells
drive a cellular response, send signals for more production of Th2
Th2 cells
drive B-cells to make antobodies
Th17 cells
drive the innate inflammatory response
CD4 cells subdivisions
Treg
Th1
Th2
Th17
Thymus
-all generation of the T cell diversity occurs in the thymus before birth or straight after birth
Hemopoietic lymphoid precursors migrate from the bone marrow to
the thymus where they mature into T lymphocytes
They “see” self in the thymus -MHC
Only a small percentage of T cells survive the thymus as mature T
cells. Most die from “neglect”. Do not get to recognize the self. Some recognise self too strongly and get killed
How does the immune system detect the virus that is growing inside the cells?
-uses MHC
MHC
polymorphic
Major Histocompatibility complex( MHC)
-controls tissue rejection( different MHC in people–> tissue will get rejected)
why can tissue transplants be done now?
- can find the close match of MHC
- recipient might have to take immunosuppressant drugs for the rest of their life
- Still cannot transplant skin bcause skin has unique cells, typically antigen presenting cells in the skin that generate this profound immune response.
How can T cells recognize own cells as foreign( eg tumor cells)
• Cytotoxic T cells (CTL) react to your own cells when there is a change in MHC
class I molecules – i.e. when they express a “neo-antigen” picked up from
inside the cell.
• This “neo-antigen” could be a viral or altered self antigen.
The T-cells are engineered to recognize the neo-antigens on the surface of the cancer cells
THE BASIS OF IMMUNOTHERAPY
How can T cells recognize own cells as foreign( eg tumor cells)
• Cytotoxic T cells (CTL) react to your own cells when there is a change in MHC
class I molecules – i.e. when they express a “neo-antigen” picked up from
inside the cell.
• This “neo-antigen” could be a viral or altered self antigen.
The T-cells are engineered to recognize the neo-antigens on the surface of the cancer cells
THE BASIS OF IMMUNOTHERAPY
Mouse genetics to identify the MHC locus that controlled tissue rejection
Experiment carried out in 1974:
*congenic mouse strain-a mouse that has been developed through the process of backcrossing. And they do that so that they can isolate sets of genes from all the other genes that determine this functional activity and the functional activity that used to generate these congenital strains is this tissue rejection.
-took 2 strains of mice ( A and B) that clearly had the phenomenon of tissue rejection. Mate A and B–> AxB. Then mate A x B (progeny) with B(parent). Then the next progeny AxBxB get tested on tissue rejection. Then get mated with B again and tested for tissue rejection again. This is repeated only with the mice that still reject the tissue.
After about 20th backcross, the progeny will have all the genes from B and none from A.
So the only difference between the 19th progeny and the parent B strain is the MHC(tissue rejection complex)–> that’s how they isolated MHC complex.
MHC restriction experiment
took 2 congenic strains of mice that have been backcrossed. The only difference between them is the MHC gene, all the other genes were the same. Still rejected each other’s tissue.
- infected the mice with the same virus
- after ~ week, took the spleens out and isolated the lymphocytes
- did cytotoxic killing essay( They looked at the ability of the T cells from one strain of mice to kill virus-infected cells from the conjoined strain.)
- FOUND: T-cells from one mouse strain did not kill the infected epithelial cells from the other mouse and vice versa.
-recognition of virus/pathogen was regulated by MHC
MHC Restriction: T cells recognize two components the self component, which is MHC and the non-self component, which was viral peptide.
Viral immunity is restricted by the MHC complex!
Image of T cell and MHC
MHC CLass 1 structure
-2 chains: heavy chain + beta2 microglobulin
the polymorphism that we find in these MHC molecules occurs along the top two alpha-helices. In the floor of the top grove.
peptide sits in the middle of the grove( self-peptide, tumor or viral peptide)
A, B, C types
Everyone has all 3 types in pairs. 2xA, 2xB, 2xC( heterozygous at all 3)
MHC class 2
alpha and beta chains
MHC class 2
alpha and beta chains
What tells the T-cell that a cell is different?
the combination of the peptide and the MHC ( self + non-self)
CD4 and CD8
accessory molecules on T-cells
important in defining whether the T-cell will become a cytotoxic T-cell or a helper cell
CD4 and CD8 have intracellular tyrosine kinases associated with
their cytoplasmic tails that initiate T cell signaling through
phosphorylation. They are crucial to the activation of your
adaptive immune response.
CD4 t -cells
helper T-cells recognize the antigens in MHC class II antigens in MHC class II
eg a macrophage phagocytosing, bits of bacteria peptide get into MHC class 2 are presented to CD4 t-cells, generates helper t-cells response. DO NOT want CD8 to kill the macrophage.
CD8 t-cells
• CD8 = Cytotoxic T cells recognise antigens in MHC class I.
eg virus infecting an epithelial cell, bits of the virus get into MHC class 1 and presents the peptide to CD8, CD8 then kills the infected cell.
MHC class vs class 2
MHC class 1 is found on all cells in the body, except RBC
MHC class 2 is only found on antigen-presenting cells( cells that are able to undergo phagocytosis- macrophages, neutrophils, dendritic cells)
So for MHC class one, the primary source of these neoantigens comes from intracellular sources. For MHC class 2- mainly extracellular pathogens
MHC polymorphism
- MHC amino acid sequences vary greatly across the population.
- There are hundreds of different variations at each MHC locus.
- Polymorphism is restricted to the protein domains that form the peptide groove –
- An individual expresses both maternal and paternal genes 2 x 3 MHC class I (A, B, C) and 2 x 3 MHC class II (DR, DP, DQ) molecules.
-MHC is Co-dominant. A total of 12 polymorphic molecules are expressed on your cells.
• No two people share exactly the same MHC profile (identical twins excluded).
what chromosome is MHC locus found on?
12
Why is MHC so polymorphic?
it generates massive diversity in the ability to recognize as many different
peptide antigens as are likely to present in your entire antigenic universe throughout your lifetime.
Not about gene rearrangement.
The reason that’s polymorphic is because of the diversity of the population diversity means that the population will survive against new pathogens that arise.
important consequences of MHC polymorphism
- Tissue transplantation is difficult except between identical
twins. - MHC polymorphisms are strongly linked to many
autoimmune diseases. Most of the disease susceptibilities are linked to the MHC locus.
MHC disease associations
if you have Addison’s disease, you’re about four times more likely to be HLA B eight.(haplotype)
So what typically happens in type one juvenile diabetes is the patient who has DR 3/4 will have a viral infection, and we still don’t know what that viral infection is. And there’ll be a viral peptide that will be presented by three and four and that will stimulate these T cells. Now, unfortunately, the stimulation works so effectively that those T cells lose the ability to lose tolerance for self, and they then start to attack normal tissue. That’s not expressing that peptide.
And that’s what causes the destruction of the beta islet cells in your pancreas that produces insulin that results in type one juvenile diabetes.
