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Lecture 6 - T cell development and MHC
Terms in this set (66)
Summary of the T cell classes
Where do T cells mature?
The thymus is a _____________ lymphoid organ that is situated in the ________________ _____________________
The thymus is a primary lymphoid organ that is situated in the anterior mediastinum
When thymus fails to develop resulting in absence of circulating T cells.
immature T cells in the thymus
How are t cell receptors (TCRs) in maturing thymocytes formed?
by rearrangement of TCR genes
double negative thymocytes
earliest cells in t cell development, do not express CD4, CD8
double positive thymocytes
single positive thymocytes
CD3+4+8- or CD3+4-8+
what are the two lineages of thymocytes (according to their TCR)?
α:β TCR cells- CD3+4+8+ double positive---> either 4+ or 8+ single positive cells
γ:δ TCR cells- minor population in periphery, CD3+4-8-
-if thymocyte TCR engages in low-affinity binding with non-self peptide presented by TEC it is rescued from apoptosis
-no engagement of TCR with non self peptide molecule---> apoptosis
Thymic epithelial cells (TECs)
present non self or self peptides via MHC molecules for positive/negative selection of thymocytes
if thymocyte TCR binds to self peptide presented by TEC with high affinity/avidity it undergoes apoptosis
what is the epitope of a t cell?
short linear peptide presented by MHC molecule
Can T cells recognise antigens without them being bound to MHC molecules?
No, only B cells and other innate cells that can do that
which MHC molecule does CD8 bind to
MHC class I
which cells in the body express MHC class I?
all nucleated cells (so RBCs do not express MHC class I)
which type of pathogen does MHC class I present?
intracellular pathogens, usually viruses
intrinsic, endogenous antigen
which MHC molecule does CD4 bind to?
MHC class II
which cells express MHC class II?
macrophages, B cells, dendritic cells
& thymic epithelial cells
Are CD4+ T cell subsets defined on the basis of the cytokines they secrete and on their effector functions?
which t cell subtype (th1 or th2) stimulate cell-meditated immunity?
secretes cytokines that activate macrophages
which t cell subtype (th1 or th2) stimulate humoral immunity?
th1 and th2 cells
th2- activates naiive b cells and induce class switching of activated b cells
describe structure of t cell receptor
disulphide linked heterodimer with V and C domains
V-alpha, V-beta, C-alpha, C-beta
V domain contains a hypervariable domain with three complementarity determining regions
what are some differences between bcr and tcr in terms of where theyre found?
tcr only found on plasma membrane and is not secreted whereas bcr is secreted into extracellular fluid
what is the antigen binding/ recognition site of tcr?
ag recognition site is at CDR3- the third complementarity determining region
ag-binding site is at the juxtaposition of the V domains
T cell receptors concentrate diversity in the __________ hypervariable region
What genes contribute to the third hypervariable loop (CDR3)?
The D and J genes
What forms the centre of the an:gen-binding site of the TCR and mainly contacts the unique pep:de component within the MHC/ pep:de complex?
pan t cell marker- found on all mature t cells
2 chains of CD3 found on either side of TCR and act as signaling complex
composed of 4 invariant chains: γ, δ, ε, and ζ
What is the TCR cell-surface an:gen-binding chains associated with a homodimeric ζ cytoplasmic tail, which contains immunoreceptor tyrosine-based ac:va:on mo:fs (ITAMs)
immunoreceptor tyrosine-based activation motifs (ITAMs)
found on homodimeric ζ cytoplasmic tail of TCR and CD3
ITAM Tyr residues are phosphorylated as a first step in T cell activation, , when the TCR contacts peptide/MHC
γδ T cell receptor
bind to heat shock proteins and nonpeptide ligands
May not be restricted by Classical MHC Class I and Class II molecules
May bind to free antigen and/or may bind to peptides presented by non-classical MHC
what are the four gene loci that encode t cell receptors?
V-alpha and J-alpha
V-beta, D-beta, J-beta
For αβ TCR variable domain which loci has more variants/diversity?
TCR-beta, therefore there are more TCR domains for V-beta than there is for V-alpha.
TCR-beta has a D loci as well
recombination is an uncontrolled and _____________ process
recombination is an uncontrolled and random process
Discrete segments are joined by ____________ during T cell development
are functional α- and β-chains generated in the same way that complete Ig molecules are generated (flanked by spacer recombination signal sequences; recognized by same enzymes)
TCRα locus (chromosome 14) consists of ________ Vα, _______ Jα gene segments, ____ C gene
70-80, 61, 1
TCRβ locus (chromosome 7) has ___ Vβ gene segments located distantly from ____ clusters each containing ___ Dβ, ___ Jβ, ___ C gene
52, 2, 1, 6 or 7, 1
which antigen do MHC class II molecules present?
MHC Class II molecules present extrinsic or exogenous antigen -ingested from the immediate extracellular environment
which antigen do MHC class I molecules present?
MHC Class 1 molecules present intrinsic or endogenous an:gen - an:genic pep:des from viruses or other intracellular pathogens - to CD8+ cytotoxic T cells
Difference in the expression of MHC class 1 and MHC class 2 between tissues?
MHC Class I expressed on all nucleated cells, most highly expressed in haematopoietic cells. MHC Class II expressed by professional antigen presenting cells
human MHC locus is located on chromosome ____ and has two alleles from each parent.
human MHC locus is located on chromosome 6 and has two alleles from each parent.
which genes are MHC class 1 molecules encoded by
HLA- A, -B, -C
which genes are MHC class II molecules encoded by
HLA -DR, -DP, -DQ
Each expressed MHC protein can bind a range of peptide antigens (T/F)
HLA-E, HLA-F, HLA-G, HLA-H are class Ib genes and they are ______ polymorphic than A, B, and C locus gene products
HLA-E and HLA-G gene products are involved in ....
recognition by NK cells
Each MHC locus has many alleles (variant genes that occupy the same loci and encode variants of the MHC protein). The expressed MHC molecule determines....
which peptide antigen the cell can bind and present for surveillance by CD4 and CD8 T cells
Human MHC genes are _________ polymorphic especially for MHC class I
Human MHC genes are highly polymorphic especially for MHC class I
Expression of MHC alleles is ___________________
Expression of MHC alleles is codominant
Variation arising from genetic polymorphism is usually in the ____________ . Such variation can alter the specificity of an MHC molecule for a peptide antigen
how does variation of MHC genes affect the MHC molecule?
affects amino acid sequence of MHC molecule
can alter the specificity of an MHC molecule for a peptide antigen
some alleles are better at recognising certain antigens than others
describe the structure of MHC class I molecule
The α chain folds into 3 domains: α 1, α2, and α3. The α 1 and α2 domains form the antigen-binding groove/ peptide binding cleft
B2 microglobulin bind to α3 domain and acts as stabilising molecule, B2 microglobulin not part of MHC gene loci
Peptides (8-10 aa long) are stabilized at both ends of the groove by binding to invariant sites
describe the structure of MHC class II molecule
heterodimers of α and β chains, α1, α2, β1, β2
Peptides are at least 13 aa long
Ends are not bound to groove; peptide is held in place by interactions along its length
Summary of Major Features of MHC
Characteristic motifs distinguish peptides which bind to different MHC molecules. Describe how
• Class I MHC molecules typically have 6 pockets in the peptide-binding groove, with side chains from the peptide anchor residues extending to fill the pockets; MHC Class II molecules have similar peptide binding specificities
• MHC molecules therefore bind peptide antigens with amino acid sequences that comply with the MHC binding requirements
• As shown in the table, this means that a particular microbial protein can be scanned to check for amino acid sequences which 'fit' a particular MHC molecule
• These bioinformatics approaches are widely used in assessment of pathogen-specific T cell immunity ( for eg. Epitope prediction in vaccine design)
with variation in MHC molecules in individuals how are they made to recognise a particular antigen
amino acids in recognition sites are highly conserved
The TCR recognizes a complex of self-MHC and an antigenic peptide. A T cell specific for peptide x and a particular MHC molecule A will not recognize the complex of peptide x with a different MHC molecule, or a different peptide y in the context of MHC A
t cell recognition of antigens is dependent on ________
t cell recognition of antigens is dependent on MHC molecules
how do CD4 and CD8 molecules on T cells help with interaction of TCR and MHC/peptide?
CD4 and CD8 molecules on T cells stabilize interaction of TCR and MHC/peptide
CD4 and CD8 bind to the__________________________ of the MHC Class I and II molecules and leave the upper surface of the MHC molecule exposed and free to interact with a T cell receptor
membrane proximal domains
Superantigens are molecules produced by many different pathogens, including bacteria, viruses, and mycoplasmas
They are recognized by T cells without being processed into peptides and presented by MHC
Bind to the outside surface of MHC Class II
Stimulation by a superantigen causes the CD4+ T cell to release very large amounts of cytokine and activate many cells- can be fatal
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