L4 Histocompatibility complex and antigen presentation Flashcards
List 3 professional antigen
presenting cells (APCs)
Dendritic cells
Macrophages
B-cells
What unites microbial fragments in antigen presentation
glycoproteins – major histocompatibility (MHC) proteins and presented at the cell surface
MHC-microbe specific peptides present what to trigger what?
The MHC-microbe-specific peptide complex will then be presented to T lymphocytes, triggering adaptive immune responses
T-cells only see what
peptides in context of MHC molecoles
MHC prime t-cells
MHC activate t-cells
T lymphocytes only see peptides on what condition
T lymphocytes can see only peptide fragments of protein antigens, and only when these peptides are displayed on host cell surfaces bound to MHC molecules
T cell–mediated immune responses is generated only against protein antigens that are either produced in or taken up by what?
host cells
what do Naive T lymphocytes see to initiate clonal expansion and differentiation
Naive T lymphocytes see protein antigens presented by dendritic cells to initiate clonal expansion and differentiation of the T cells into effector and memory cells
Histo- meaning
tissue
What is the Major Histocompatibility
Complex?
▪ Collection of genes encoding proteins that enable the host to distinguish self and non-self
▪ MHC molecules were first discovered as proteins encoded by the murine MHC locus involved in graft rejection - hence histo (tissue) compatibility (to get along)
▪ The MHC complex includes more than 200 genes and have many possible variations
What are some transplants rejected?
Transplantation of cells or tissues from one individual to a genetically nonidentical individual invariably leads to rejection of the transplant because of adaptive immune responses.
Molecules responsible for transplants rejected?
MHC molecules that bind and present peptides to T cells.
Heterozygous individuals will pass down MHC to offspring explain probaility
offspring will receive one of four possible combinations of the parental MHC haplotypes. Siblings are also likely to differ in the MHC alleles they express, there being 1/4 chance that an individual will share both haplotypes with a sibling.
Percentage for siblings to have matching MHC haplotypes
25%
Haplotype
a set of DNA variants along a single chromosome that tend to be inherited together.
What genes are polygenic and highly polymorphic
MHC
The human MHC region is also called the
Human leukocyte antigen (HLA)
Can individuals present and respond to different microbial peptides
Yes
What is further amplifed because HLA genes are codominant
Variation
Variation is further amplified because HLA genes are codominant
Both parental alleles of each MHC gene are expressed
MHC-peptide: Broad Specificity
Different peptides can bind to the same MHC molecule but not at the same time
MHC-peptide: One at a time
A t-cell only response to a single peptide bound to an MHC molecule
MHC
Major histocompatibility Complex
Proteasome
complex intracellular proteases that function in regulated degradation of cellular proteins
MHC-peptide: Stable surface expression of bound peptide
Only the peptide loaded MHC molecules are expressed on the cell surface for recognition by T-cells
MHC-peptide: Very slow off-rate
MHC molecules displays bound peptide for long enough to be located by T-cel;
T-cell recognition of antigens is MHC restricted
T-cells depend on the presence of MHC molecule in the APC and co-recognisiton of foreign peptide and MHCm called MHC restriction
MHC restricted
Co-recognition of a foreign peptide and an MHC molecule is known
How are T-cells and MHC specific?
A T cell recognises antigen as a peptide bound by a particular allelic variant of an MHC molecule and will not recognise the same peptide bound to other MHC molecules.
Explain how MHC are polygenic
The genes of the MHC exhibit genetic variability; and the MHC has several genes for each class hence it is polygenic.
Explain how MHC are polymorphic
The MHC is also polymorphic, meaning a large number of alleles exist in the population for each of the genes.
Class I MHC molecules
- Identify all nucleated cells of the body as “self”
- No RBC
- Class I MHC molecules span the membrane of almost every cell in an organism
Class I MHC molecules characteristics
▪ Bind to normal (self) peptides and antigens extracted from intracellular pathogens (e.g., viruses) – signalling to the immune system that it is an infected host cell
▪ Smaller binding pocket
▪ Endogenous antigen processing
Class 1 MHC genes
Class I: HLA-A, HLA-B, and HLA-C.
Why are CD8-T cells important wil Class 1 MHC
Class I MHC molecules are recognized by CD8+ cytotoxic T-lymphocytes (Tc cells)
* Tcyt Cell (cytotoxic T cell) has specificity towards cells containing peptides associated with Class I MHC due to the presence of CD8 antigen on the surface of Tcyt Cell.
* CD8 Recognize peptides on infected cells presented by MHC-I
Class II MHC molecules
▪ Expressed by professional antigen presenting cells
▪ Bind to antigens degraded as a consequence of phagocytosis or receptor mediated endocytosis (extrinsic or exogenous antigen)
▪ Larger and deeper pocket ▪ Exogenous antigen processing
How do dendritic cells become activated
They capture antigens
Process of dendritic activation and migration
▪ Dendritic cells (DCs) capture antigens and become activated
▪ Upon activation, DCs lose adhesiveness for epithelia & peripheral tissues and begin to migrate through lymphatic vessels to the lymph nodes where it collects antigens
▪ During migration DCs start to mature by increasing synthesis and stable expression of MHC molecules, and other costimulatory molecules like CD80/CD86 (B7-1/B7-2)
How Dendritic cells work against pathogens? (Immunity)
▪ Immature DCs undergo maturation in presence of antigens (or cytokines)
▪ activates its metabolic, cellular and gene transcription causing it to move (MIGRATE) from peripheral tissues to Lymphoid organs.
▪ Loose adhesiveness to epithelia and peri-tissues and increase motility
▪ increase expression of MHC-II and costimulatory molecules.
Antigen presentation to naïve T cells in the initiation of T cell responses to protein antigens
Numerous cytoplasmic processes and high surface area allows intimate contact with many surrounding cells - e.g.,
experimentally, only one mature DC is required to stimulate 100 - 3000 T cells
MHC I pathway
▪ cytosolic protein antigens are degraded in the proteasome, and transported from the cytosol to the ER,
▪ where MHC-I molecules receive peptides and bind.
▪ Stable complexes of MHC-I molecules with bound peptides move out of the ER, through the Golgi complex, to the cell surface.
▪ For recognition by CD8 +
T cells
What are MHC I and II expressed by
[1] by all nucleated cells and interact with CD8+ T cells.
[2] by APCs and interact with CD4+ T cells.
MHC II pathway
▪ protein antigens are internalised into endosomes, and proteolytically cleaved by enzymes in lysosomes and late endosomes.
▪ protein antigens that are degraded in lysosomes bind to class II MHC molecules for recognition by CD4 + T cells
▪ MHC-II molecules are transported from the ER to endosomal vesicles.
▪ The peptides generated from extracellular proteins bind to class II MHC molecule
▪ the complex moves to and is displayed on the surface of the cell.
Superantigen
- Toxins that can directly interact (w/o prior processing) with MHC-II molecules
- Will lead to massive T-cell activation and cytokine release (can cause inflammation)
- Toxic shock syndrome toxin-q and staphylococcal enterotoxins
Antigen Cross presentation
- DCs transport ingested antigens (that were going to go through the MHC-II pathway) into the cytosol.
- Antigens are processed and mounted on MHC-I molecules
- Cross-presentation is essential for the initiation of cytotoxic CD8+ T cell responses when DCs are not directly infected
▪ Dendritic cells are able to ingest infected host cells, dead tumour cells, microbes, and microbial and tumor antigens
