MCM 2-3 T-Cell Receptors & MHC Flashcards
describe the TCR
T-Cell receptor consists of two chains (alpha and beta), linked by a disulfide bond.
both chains are glycoproteins and contain both constant and variable regions
difference between TCR and BCR expression
unlike BCRs, TCRs are not soluble. they only exist on cell surface as a transmembrane receptor
The t-cell receptor has no ______
effector function
compare the diversity and binding affinities of TCR and BCR
TCR have greater total diversity (100,000x) than BCR, but binds antigens less tightly than BCR
unlike BCR, in TCR there are no ________
somatic hypermutations
describe the TCR complex
TCR is found on the cell surface associated with other proteins, 8 polypeptides called the TCR complex
alpha/beta chains - bind antigen, form the core TCR. they associate with
- one copy each of CD3gamma and CD3delta
- two copies each of CD3epsilon and CD3zeta chain
The TCR (alpha beta subunits) itself is responsible for
recognizing antigens, is unable to signal transduce because of very short cytoplasmic tail
interactions with all of the CD3s within the TCR complex allow for signal to be transmitted
what purpose do the CD3’s of the TCR complex serve?
- allow signal transduction
2. transport of newly synthesized TCR to the surface
MHC molecules in humans are called
HLA - Human Leukocyte Antigen
What do MHC molecules do and what do they consist of?
they present antigen to T-Cell Receptors
they consist of 2 types of chains, either alpha or beta
describe MHC1
where is most variability?
what do they do?
what are some important ones?
consists of three alpha subunits (a1,a2 which make the groove, and a3 which is attached to the cell membrane and associates with Beta subunit)
most variability in this class is in groove region where peptide binds (alpha-2 is where most variability exists)
-bind shorter peptides
they present antigen to CD8+ T-cells (during T cell development, CD8+ cells are selected to bind Class 1)
Important class one molecules include HLA-A,-B,-C
describe MHC2
where is most variability?
what do they do?
what are some important ones?
consists of two chains (alpha (a1,a2)/beta (b1,b2) with most variability located in the beta chain
-can bind longer peptides
present antigen to CD4+ T-Cells (during T-Cell Development, CD4+ cells are selected to bind Class II)
HLA-D,-Q
describe the features of antigens determine how they bind to or are recognized by MHC1 or MHC2
- while there are specific variable regions in come class1/class2, peptides only need to have a specific anchor reside to bind those regions
- anchor/contact residues (binding motif) are conserved for binding of the peptide to the MHC. Once bound, the other amino acids can be presented to a T-Cell
MHC1 are found where and do what?
found on all nucleated cells (not RBCs)
present CYTOSOLIC antigens to CD8+ T-cells
MHC2 are found where and do what?
found on antigen presenting cells
presents to CD4+ T-cells antigens that are found on..
- intravescular pathogens (like mycobacteria and other intracellular bacteria)
- pathogens taken up from extracellular environment through receptor mediated endocytosis or phagocytosis
Antigen processing for presentation by MHC1
Viral infection example
- viral proteins recognzed, poly-ubiquinated which marks for degredation by proteasome.
- proteins fragmented into peptides 8-10 aa long
- peptide bind to protein called TAP (transporter of antigen presentation) in the membrane of the ER
- TAP:Peptide complex moves to lumen of ER
- peptide is placed on MHC1 binding groove, displacing self-peptide placeholder
- MHC:peptide moves to cell surface to be recognized by CD8+ T-cell
where are MHC Class I molecules expressed?
on all nucleated cells. RBC’s-erythrocytes have no nucleus so would not express MHC1
Antigen processing for presentation by MHC2
- RME/Phagocytosis ingested antigens taken into phagolysosome and fragmented into by protease (slightly longer peptides than MHC1)
- peptides move to endosomal compartments and placed into binding groove of MHC2 (displacing CLIP “Class 2 associated invariant chain peptide” which binds MHC2 to prevent binding of self-peptide fragments
- MHC2:peptide carried to cell surface, recognized by CD4+ T-cells
Where are MHC2 molecules found?
subset of hematopoietic cells that are professional antigen presenting cells (APCs)
- dendritic cells
- B cells
- Macrophages
what is cross presentation?
the process that allows processing of antigen for binding to both MHC1 and MHC2 in antigen presenting cells
antigen presenting cells have both MHC1 and MHC2 as they are both nucleated(MHC1) and antigen presenting (MHC2)
What must the TCR recognize in order to bind?
must recognize both the MHC complex and peptide
recognizing one is generally not enough
must be correct MHC and peptide
describe the special case of allo-reactivity
when the immune response is activated during transplant rejection, binding of TCR to antigen may not require the simultaneous binding to peptide antigen AND MHC
Polymorphism of the classical MHC loci is due to
allelic variation in the number of allotypes - this produces many HLA types
what is an allotype?
allotype is the allele of the antibody chains found in the individual.
main distinguishing factor between classical and non classical MHC molecules?
polymorphism
MHC molecules are highly polymorphic due to
polygeny of MHC and the codominant expression of MHC genes
two factors that result in large number of different MHC molecules all expressed on the surface of cells
- Allellic variation in the number of allotypes, producing many different HLA types, leads to high levels of MHC polymorphism
- Polygeny - there are several different MHC genes with similar functions
Polymorphism and polygeny
what is an MHC haplotype
why is it important to have more MHC haplotype heterozygosity?
the complete set of alleles (varient genes that can occupy a single locus) found within an animals MHC
everyone has a different MHC haplotype
-you will be able to recognize and present more foreign antigens on cell surface - allows you to activate more pathogen-specific T-CElls (explains inbred population susceptibility to certain diseases/infections, they generally have homozygosity)
how are MHC alleles inherited and expressed?
benefit?
one from each parent, codominant
codominant expression of both alleles will allow presentation of more peptides from any pathogen than more related haplotypes so are able to activate more pathogen-specific T cells and better protect against infection
more polymorphic or divergent haplotypes will allow…
presentation of more peptides from any pathogen than more related haplotypes so are able to activate more pathogen-specific T cells and better protect against infection
strong associations between certain HLA types and
autoimmune diseases, some are also protective for certain diseasess
Gamma/Delta TCR
expressed where?
diversity level?
what do they do?
expresed on surface of CD4-/CD8- cells
less diverse than alpha/beta
function unclear
what do superantigens do?
function as bridge between certain TCR variable genes and MHC
no antigen processing/presentation necessary by MHC for binding to TCR
Frequency of superantigen specific T-cells vs conventrional antigen T-cells?
superantigens include…
T-cells specific for superantigens occur at higher freuqnecy than for conventional antigens
bacterial enterotoxins, staph, strep, mycobacterial
effect on presenting cell
MHC1
MCH2
MHC1 - presenting cell is killed
MHC2
i. If Intravesicular pathogens: presenting cell (Macrophage) is activated to kill intravesicular bacteria (mycobacteria and other intracellular parasites) and parasites
If extracellular pathogens and toxins: presenting cell (B-Cell) is activated to secrete Ig to eliminate extracellular bacteria/toxins
gamma:delta is…(4)
recognition of antigen is not restricted by MHC expressed on CD4-CD8- t-cells function unclear - possible tissue homeostasis
superantigens
-function as bridge between certain TCR-V genes and MHC
- include bacteria exotoxins - staph, strep, myco
- no antigen processing or presentation by MHC required for binding to TCR
- t cells specific for superantigens occur at higher frequency
- activation of many t-cells = cytokine storm
how does a helper T cell interact wiht macrophage?
CD4
Relative Risk (RR)
MHC+/- in individuals WITH disease vs WIHOUT disease
RR1 of 1 = allele is expressed with same frequency in the patient and population, confers no increased risk
RR greater than 1 = indicates association of allele with disease
