T lymphocytes and antigen recognition Flashcards
What is most likely to determine an individual subject’s HLA type?
inheritance from parents
How many alleles in total are inherited from parents for HLA determinants?
12:
* MHC I: 2 each of HLA A, B, C
* MHC II: 2 each of DP, DQ, DR
What are the 3 HLA classes which are major determinants of the HLA phenotype?
A, B DR
What are the 2 key functions of T lymphocytes?
- destroy intracellular pathogens
- TCR recognises small peptide fragment of antigen presented by MHC molecules on the surface of host infected cell
What is the T cell receptor analogous to in B cells?
membrane-bound Fab portion of antibody
Where are the variable and constant regions of T cell receptors?
variable = towards N terminus
constant = towards the membrane
How does the TCR influence intracellular signalling?
cytoplasmic tail too short for signalling; polypeptides associate with CD3 polypeptides with longer cytoplasmic domains (gamma, delta, episolon and zeta CD3 subsets)
What are the 2 major populations of T cells and their roles?
- CD4+: T helper cells, see peptides on MHC class II (class II restricted)
- CD8+: cytotoxic cells, see peptides on MHC class I (class I restricted)
What process increases the avidity of T cell target cell interaction?
co-receptor molecules bind to the relevant MGC
What are 3 functions of CD8 T cells?
- cytotoxic, kill target cells
- secrete cytokines
- induce apoptosis in the target cell
What are 5 overall functions of T helper cells (CD4)?
- secrete cytokines
- Recruit effector cells of innate immunity
- help activate macrophages
- Amplify and help Tc and B cell responses
- MHC molecules present antigen fragments at cell surface
What are 2 key types of T helper cells (CD4) and their respective roles?
- CD4 Th1: activate macrophages
- CD4 Th2: amplify antigen-specific B cell response
What are T cell precursors called and how do they develop?
progenitor cells: develop in bone marrow then migrate towards the thymus in the circulation; once mature leave thymus travel around body in the circulation
Where in the thymus does T cell maturation occur?
from cortex to medulla
How do T cell progenitors develop to CD4 and CD8 T cells?
- initially express neither (CD4 or 8) i.e. double negative; in the cortex, T cells express a TCR precursor (pre TCR; β + “surrogate” αTCR).
- then become double positive -express both CD4 and CD8
- in the medulla, many different αβTCR’s created by gene rearrangement
- generated TCRs express either CD4 or 8 - single positive
How does DNA get rearranged to develop the TCR protein?
germline DNA coding alpha and beta separately undergo rearrangement and recombination
What maintains the selection process of T cells in the thymus meaning only useful cells leave the thymus?
Checkpoints - occurs during interactino with macrophages and dendritic cells within the thymus
What are the 2 checkpoints in the thymus that ensure selection of T cells?
- Pre-TCR checkpoint: is new β chain functional? no -> apoptosis
- Post-TCR checkpoint: is αβ TCR functional? Is it dangerous/autoreactive? no; / yes -> apoptosis
What is negative selection?
T cells which see “self”, i.e. host molecules – receive signal to die by apoptosis
What is positive selection?
T cell receptor binds weakly to MHC molecule – receive signal to survive
What proportion of thymocytes survive selection?
5%
What is the function of MHC molecules?
present antigens to T lymphocytes
What is the structure of the MHC class I molecule?
- 2 non-covalently associated polypeptide chains
- Heavy: α1, α2¸ α3 – these are transmembrane
polypeptides with a peptide binding, immunoglobulin like
and cytoplasmic region - Light: β2-microglobulin – this only consists of an
immunoglobulin like region - α1 and α2 are joined by PEPTIDE BINDING GROOVE
What are the 2 chains and their associated regions forming MHC I?
- heavy chain: alpha 1-3 polypeptides
- light chain: beta-2 microglobulin
Whcih polypeptides of MHC class I are joined by the peptide binding groove?
alpha 1+2
Which part of MHC class I does CD8 interact with?
the alpha-3 domain
What is the structure of MHC class II molecules?
2 transmembrane polypeptides of equal length, alpha and beta, each with 2 domains, alpha 1+2, beta 1+2
Which part of the MHC class II molecule does CD4 interact with?
beta 2
What are 3 characteristics of peptides accommodated by MHC class I?
- peptides of 8-10 amino acids
- peptides are buried within the structure
- peptides all same length
What are 2 characteristics of peptides accommodated by MHC class II?
- peptides >13 amino acids
- peptides stick out from MHC molecule
How do MHC molecules overcome there being relatively few MHC but needing to present many peptides?
they present subsets of peptides using binding motifs
What is abinding pocket?
certain residues (anchor residues) are directly associated with the peptide due to their specific sequence; useful to predict which peptides will be presented
How many functional genes code for HLAs?
128 (only 40% immune related)
What is meant by the term co-dominant when referring to expression of MHC genes?
both materna and patern MHC is expressed
Which cells express MHC class I?
all nucleated cells, levels may be altered during infection or by cytokines
Which cells express MHC class II?
only professional APC (B lymphocytes, macrophages, dendritic cells), may be regulated by cytokines
What is meant by polymorphism in reference to MHC molecules?
large nuber of alternative different versions of the same gene within the population, termed an allele
What does an MHC haplotype refer to?
each group of MHC alleles linked on one chromosome
What are the most polymorphic HLA forms in each class of MHC (I and II)?
- I: B
- II: DR β
In what form do T lymphocytes recognise antigens?
only processed antigens that are presented on cell surfaces by MHC molecules
How is endogenous antigen dealt with?
processed is antigen synthesised within the APC; is taken to CD8
How is exogenous antigen dealt with?
synthesised outside the APC, can be taken up by macrophage etc, taken to CD4
What are 4 stages of producing class I MHC?
- antigen is cleved by proteasome, taken into rough endoplasmic reticulum by Transporter Associated with antigen Presenting (TAP)
- Binds with MHC class I
- chaperones e.g. calnexin help protein polding
- then trafficked by golgi to the surface
What are 6 stages of producing MHC class II?
- antigen endocytosed
- cleaved by proteases
- MHC II migrates into rough endoplasmic reticulum and associates with the invariant chain
- the MHC II-invariant complex is migrated into the golgi in the endosome
- invariant chain is digested by CLIP (class II associated invariant chain peptide)
- CLIP is then exchanged for the antigenic peptide, which is then presented at the surface
What is a Gamma delta (γδ) T cells?
small subset of CD3-positive T cells in the peripheral blood but occur at increased frequency in mucosal tissues - have TCR composed of gamma and delta chains, don’t require MHC to present antigen peptide, exist in epithelium peripherally
What type of antigenic material is presented by MHC class I?
intracellular
What type of antigenic material is presented by MHC class II?
extracellular
