Antigen presentation and T lymphocytes Flashcards
Major histocompatibility complex (MHC) molecules: recall the outline structure, cellular distribution and functions of major histocompatibility complex (MHC) class I and class II molecules Antigen presenting cells (APCs): list examples of antigen presenting cells, explain the mechanisms by which they process and present antigens, and list their locations T lymphocyte subsets: summarise the origins and functions of T lymphocyte subsets T lymphocyte activation: explain the importance of antigen
Why are T lymphocytes important when we have B cells and antibodies? (x2 points)
T-cells detect and combat INTRACELLULAR pathogens (B cells work in the circulation). Antibodies can only destroy EXTRACELLULAR pathogens but cannot get inside cells.
What do T cell receptors detect (TCR)?
Detect antigens (presented as a peptide fragment) on MHC molecules – they therefore detect infected cells. BIND TO THE MHC COMPLEX.
What is the structure of a T cell receptor? Associated with?
Analogous (similar) in structure to FAB region of an antibody (shown by the photo). There is an alpha and beta chain (these are both immunoglobulin domains – a SMALL number of TCRs use gamma and delta chains instead) with variable and constant regions. Charged residues in membrane allow for association with CD3 polypeptides (expressed by all T cells and are found near the TCR) for signalling.
What are the different types of T cell? (x2)
CD4 cell have CD4 co-receptor that recognises antigens on MHC Class II molecules – “CLASS II RESTRICTED”. CD8 cell have CD8 co-receptor that recognises antigens on MHC Class I molecules – “CLASS I RESTRICTED”. They are NOT TCRs. They are ASSOCIATED with the TCR (see photo).
What are co-receptors?
Bind to the relevant MHC (conserved part, not the antigenic peptide), increase the avidity of T cell-target cell interaction and are important in signalling.
What are alternative names for CD8 and CD4 T-cells? (x2 and x2)
CD8 = Tc or CTL (cytotoxic T lymphocytes). CD4 = T helper cells, Th.
How do the two types of T-cell destroy their target? (x2 mechanisms)
CD8: most are cytotoxic and kill target cells by inducing apoptosis in target cells – programmed cell death. They also secrete cytokines. CD4: secrete cytokines to recruit effector cells (of innate immunity), activate macrophages, amplify CD8 responses, help B cell responses, delayed type hypersensitivity, and involved in regulation – covered more in future flashcards.
What is the thymus: in relation to T cells?
Site of maturation of T cells. T-cells mature by moving from the cortex to the medulla. T-cells do originate in the bone marrow though!
What is the process of T cell development in the thymus?
□ Immature T-cell precursors arrive in cortex and are CD4-CD8-TCR- (‘-‘means negative – so do NOT express CD4, CD8 or a TCR receptor, they are just a cell!). The cell is so-called ‘double negative’. □ On arrival to cortex of the thymus, gene segments are rearranged. The first beta chain is paired up with a ‘surrogate alpha’ chain to form preTCR (hence CD4-CD8-preTCR+). This gene rearrangement is what produces the 10^10 different TCRs that are antigen-MHC specific. □ When there is a function TCR, cells express CD4 and CD8 – so are called ‘double positive’ (hence CD4+CD8+TCR+). Meaning that it expresses both co-receptors. □ In medulla, selection process occurs to remove one coreceptor by presenting to MHC Classes I and II (if TCR binds to MHC Class I, it becomes a CD8+ cell). Whichever the T-cell bounds to determines finishing cell type (CD8+TCR+ or CD8+TCR+). □ Once mature, T cells return to the blood and circulate.
How does the alpha and beta chain on a TCR compare to the heavy and light chains of an antibody? Why? How does recombination therefore happen in the alpha and beta chains?
Alpha is comparable to the light chain because it contains just VJ regions. Beta chain is comparable to the heavy chain because it contains VDJ. MECHANISM: recombination occurs using the same principles as in the BCR – look at photo. Don’t really need to know details.
What are the two thymus checkpoints?
preTCR CHECKPOINT: if the new beta chain is FUNCTIONAL (not autoimmune, for example), it survives and develops (–> CD4+CD8+TCR+). If not, then the cell dies by apoptosis. (Remember, TCR can be self-destructive because the recombination process is random.) LEVEL OF BINDING: only weakly binding abTCRs survive. Those that can’t bind MHC (termed useless – if binding is too weak, then receptor will be able to bind to the peptide (antigen), but not the MHC – binding to both is needed) or bind it dangerously (binds too strongly) are destroyed by apoptosis.
What is a major histocompatibility complex?
The MHC is a group of tightly linked genes important in specific immune responses because they present antigens to T lymphocytes. Display sample of internal cell contents at cell surface for immune cell recognition – markers of self and indicate health of cells: CONTINUOUSLY present peptides even when not infected.
What are the two classes of MHC molecule responsible for?
MHC Class I molecules – expressed on nearly all our cells, so it is the MHC Class I molecule that is responsible for transplant rejection – MCH Class I molecules on the transplanted organ holds out a sample of the internal cell contents (transplantation antigen) for CD8 T cells of the person receiving the organ. MHC Class II molecules mount an immune, antibody response – mediated by CD4 T cells.
What is the structure of MHC Class I?
Has one transmembrane and cytoplasmic region. Has three domains: alpha 1, 2 and 3 – comprising the heavy chain of the MHC. The B2-microglobulin is the light chain – NON-COVALENTLY associated with the heavy chain. The alpha 3 domain and B2-microglobulin are similar in structure to Ig – so are part of the immunoglobulin super-family. The bit that binds the peptide (the thing the MHC holds out for T cells) if between the alpha 1 and 2 regions. This region can only hold peptides of 8-10 amino acids.
What is the structure of MHC Class II?
Like MHC Class I, there are two polypeptides, but they are both the same size (one polypeptide has alpha 1 and 2, the other beta 1 and 2 – unlike MHC Class I which has alpha 1, 2 and 3, and B2-microglobulin). Has two transmembrane and cytoplasmic regions. Peptide binding region is the same. This region can hold peptides of more than 13 amino acids.
Where do the CD4 and CD8 co-receptors bind to the MHC?
CD8 bind to alpha 3 domain of MHC Class I. CD4 bind to beta 2 domain of MHC Class II. Remember, co-receptors are not found on the same cell as the MHC – the co-receptors are found on a T cell and bind to MHCs on target cells with TCR – as shown in the photo.
What are the differences between structure of MHC Class I and II? (x3)
Two polypeptides in each, though in MHC Class I, they’re different sizes (alpha 1, 2, 3 vs B2); in MHC Class II, they’re the same size. MHC Class I has one transmembrane and one cytoplasmic region; MHC Class II has two. MHC Class I can accommodate peptides of 8-10 amino acids; MHC Class II can accommodate peptides of >13 amino acids.
What is the Human Leukocyte Antigen (HLA)?
A gene complex encoding the MHC proteins in HUMANS. Found on Chromosome 6. (The HLA does not just code for MHC Class I and II molecules – they code for other proteins too.)
How are the MHC classes encoded by the HLA?
DP, DQ and DR genes encode the alpha and beta chains of Class II molecules. A, B and C genes encode the HEAVY chain of Class I molecules – HLA does not encode for B2-microglobulin because it is the same for each MHC Class I molecule sub-type. The subsequent sub-type names are given in the photo. HLA may be used interchangeably with MHC; hence why these are name HLA-DP… and not MHC-DP.
What are the characteristics of HLA genes? (x3 points)
MHC is POLYGENIC with several class I and II loci i.e. there is more than one gene locus involved in expression of MHC. Expression of MHC is CO-DOMINANT meaning that maternal and paternal genes both expressed. Human MHC genes are highly POLYMORPHIC: meaning there are lots of different alleles (thousands) for the same gene in the population. These alleles are LINKED on the SAME chromosome (Chr 6) – this collection of alleles is called MHC HAPLOTYPE.
What does polymorphism in HLA genes mean for phenotype in the population?
Means that there’s lots of phenotypic variation – explains why different people have different immune responsiveness.
Where are MHC Class I and II found? How is expression of these classes on cells regulated? (x2 and x1)
MHC class I: found on ALL nucleated cells, though levels of expression may be altered during infection, or by cytokines e.g. cytokines such as integrins upregulate MHC Class I during infection to present more antigens to the immune system = amplify response by immune system. MHC class II: found only on “professional” antigen presenting cells: may be regulated by cytokines – activated naïve T cells.
What are antigen-presenting cells?
Present processed antigens to T cells to initiate adaptive immune response. Cells include dendritic cells (skin and mucosal tissue), B cells (lymphoid tissues) and macrophages (lymphoid tissues).
What is the difference between endogenous and exogenous antigens?
ENOGENOUS: come from inside cells e.g. virus infected cells – therefore use CD8 Class I restricted T cells. EXOGENOUS: captured from external environment e.g. phagocytic cells and antigens captured and presented on B cells – therefore use CD4 Class II restricted T cells.
What is meant by an effector T cell?
An encountered antigen, that’s proliferated and differentiated into cells that participate in the host defence.
What is meant specifically by a memory cell?
A B or T cell that has encountered an antigen, contracted and ready to respond to future infections.
Why are antibodies sometimes insufficient? (x2)
Some pathogens are intracellular – antibodies are in the circulation only. Organisms evolve to escape antibody recognition – either by changing shape (influenza) or by coating antigen in a carbohydrate (HIV) or producing decoy antigens. Hence, in these cases, T cell mediated immunity is required.
How does cell-mediated immune response fight infection? (x2)
ENABLES DIGESTION OF PATHOGENS e.g. macrophages are activated by T helper cells which secrete cytokines (CD4+ effector cells). Kill infected cells – CD8+ cells are killer cells which cause apoptosis.
What do dendritic cells do in the context of cell-mediated immunity?
Dendritic cells are model antigen presenting cells that initiate T cell response. They survey tissues. When they acquire an antigen, they move to LYMPH NODES where they mature and present to T cell with an MHC Class II (because dendritic cells are ‘professional APCs’).
How do T cells travel throughout the body? Why?
They are part of the cell-mediated response – but this doesn’t mean that they have to always reside in tissues. The reason why they are involved in the cell-mediated response is because they RESPOND to pathogens in tissues.
Naïve T cells circulate through the blood, lymph and lymphoid organs to raise chance of encounter with dendritic cell (remember D cell migrates to lymph node when it captures an antigen), entering lymph nodes via High Endothelial Venules found in post-capillary venules.
What are the stages that naïve T cells go through to become memory cells – in terms of numbers?
Memory cells go through expansion and contraction stage – see photo.
Just read this flashcard:
There is a sliding scale of damage that immune cells and effector functions can do to the body, indicated by this graph. Mucous and AMPs have no damage, macrophages have the ability to be more damaging, and CTLs have the potential to damage your cells the most (because they contain apoptotic granules). As you go up the scale of potential damage, the immune system has more regulatory mechanisms – so CTLs are very tightly controlled (look earlier at 3-signal licensing response), whereas mucous secretion is not.
Peripheral tolerance: what is anergy? Common? Real-world example?
T cell recognises antigen on MHCII on a dendritic cell, but there is no/incorrect co-stimulation (one of the three things needed in the 3-signal licensing model for T-cell activation) when T-cells encounter dendritic cells presenting antigens results in shut down of T cell. This is common because most cells lack co-stimulatory proteins AND MHC Class II anyway – remember, MHC Class II are only found on professional APCs like dendritic cells. Good example is in the gut – eating something allergic may not give you a response because cells in the gut have no co-stimulatory signals, but that same allergic food may induce a response if found in the blood.
Describe the cross-regulation between the different sub-sets of T helper cells? (x2)
All the different T helper sub-sets are cross regulated by T cell cytokines. When one T helper sub-set becomes dominant, its cytokines shuts down all the other T helper cells – this focuses the immune response (e.g. if you have a viral infection, there will be a Th1 response, so Th1 will become dominant, and its cytokines will shut down Th2 and Th17). The specific cytokines that T helper cells produce also produce a different response in macrophages – again focusing the immune system on the relevant pathogen.
What are the signals required for T cell and B cell stimulation? SUMMARY
Remember the 3-signal licensing mechanism for T cells? B cells only require two of the signals.
