T cell receptor-MHC interactions

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Macrophages, neutrophils, and antibodies offer good protection against extracellular organisms, though they require CD4+ T cells for regulation. What are CD8+ T cells needed for?	Cytotoxic T cell responses against intracellular pathogens or neoplastic cells.
What is necessary in order to produce the appropriate immune response to a intracellular or extracellular pathogen (or neoplastic cell)?	T cell receptors and major histocompatibility complexes interact in order to determine whether CD4+ regulation of neutrophils/macrophages or CD8+ cytotoxicity is required.
Describe the basic structure of the T cell receptor.	The T cell receptor consists of two heterodimeric transmembrane chains (α and β in most T cells but γ and δ in mucous membranes) which in turn consist of constant and variable regions. The variable regions of a T cell receptor of a single T cell clone are specific to a single antigen - 1 naive T cell clone binds a single antigen, and all the clones are different. Between the main chains of the T cell receptor are intramembranous CD3 proteins which are 'squished together' when the T cell receptor binds antigen and its CD4+/CD8+ receptor binds MHC, resulting in intracellular signalling.
List three differences between αβ and γδ T cells.	αβ T cells are the majority of T cells expressed and their receptors interact with peptide antigens processed and presented on the surface of antigen-presenting cells, whereas γδ T cells may react with glycolipid and phospholipid antigens. Further, γδ T cells can react with antigen alone, without the necessity of MHC, and react with whole classes of antigen rather than specific antigens like αβ T cells do, meaning that their function is similar to pattern recognition receptors in innate immunity. Lastly, their binding cleft sizes result in distinct structures resulting from orientations of V and C regions - that of αβ is 147° while that of γδ is 111°, which may have an effect on their signalling mechanisms. EXTRA: Most γδ T cells lack CD4+ and CD8+ receptors entirely and are thought to be able to allow rapid reactivity to certain antigens e.g. on Mycobacterium tuberculosis without a processing step.
Why do the majority of T cell receptors (αβ) not recognise somebody else's MHC?	Because they react both with antigen and self-MHC in their recognition, and MHC is specific to individuals.
Which genes code for T cell receptors?	VDJ genes - variability, diversity, and joining. There are hundreds of different variability and diversity gene combinations, and 10's of different joining gene combinations, resulting in the highly variable antigen-binding regions of the T cell receptors.
What are the 'accessory receptors' of the T cell receptors?	CD4+ and CD8+ receptors.
How many possible VIABLE VDJ gene combinations are there in mice? Are there more or less in humans?	There are 2.9x10^20 viable recombinations, and many more non-viable combinations. There are more combinations that thin in humans as humans are more complex. Further, an organism can have a T cell receptor for almost any antigen, but not all antigens are immunogenic.
Which bodily cells have the potential to present antigen?	All nucleated bodily cells as all of these possess self MHC in their membranes, and it is the MHC complexes which present antigen.
If any nucleated cell in the body is infected with an intracellular pathogen or is neoplastic, which MHC will it present antigen with? Which T cell will bind to this?	The antigen will be presented via MHC I molecules and this will be bound to via CD8+ accessory molecules on CD8+ cells.
If a professional antigen presenting cell is presenting antigen obtained by engulfing an extracellular pathogen/its debris, which MHC will it use? Which T cell will recognise this?	Antigen in this case will be presented by MHC II molecules, which will be recognised by CD4+ T cells (helper/regulatory).
CD4+ and CD8+ accessory receptors are classed as co-receptors. What is their function in the T cell receptor-CD3 complex interaction with antigen and MHC?	The CD4+ and CD8+ receptors help to stabilise the interaction between the T cell receptor complex and the peptide-MHC complex. Another signal transduction molecule, p56-lck, binds both the CD4+ receptor and the CD3 complex, holding them closely together while the CD4+ receptor binds to the MHC molecule.
What does it mean to say that T cell responses are 'self MHC restricted'?	That the type of T cell (and its response) is dependent on which MHC class molecule it can bind to. For instance, CD4+ T cells are MHC II restricted - they only bind to antigen (usually from extracellular pathogens) presented by MHC II molecules - whereas CD8+ T cells are MHC class I restricted.
What are the effects initiated by CD4+ naive T cells binding to MHC II antigen-presenting cells?	The naive T cell differentiates into the appropriate T helper cell (Th1, Th2, Th17) to activate other immune cells. Th2 cells stimulate B cells to clonally expand and produce specific antibodies, while Th1 and Th17 cells activate phagocytes (100x more so than they may have been previously) for phagocytosis - this in turned is aided by B cell antibody production which opsonises pathogenic/infected cells.
What are the effects initiated by CD8+ naive T cells binding to MHC I antigen-presenting cells?	CD8+ T cells kill infected or neoplastic cells (if they can recognise these) directly. They use granules containing perforin and lysozyme to lyse infected cells.
Which genes encode MHC molecules in humans?	Human Leukocyte Antigen (HLA) genes.
Which proteins do 'MHC III' molecules include?	Cytokines (e.g. TNFα and TNFβ) and complement. These are also coded for by the HLA genes in humans.
What term describes a gene product that has hundreds/thousands of different variants/alleles?	Highly polymorphic
How many MHC alleles are inherited from each parent? How are these expressed?	6 from each parent - these are expressed codominantly.
Each person's MHC haplotype is unique. When might tissue typing for similarities between MHCs be important?	In transplantation therapies.
True or false: some MHC alleles are associated with an increased risk of diseases including autoimmune conditions (rheumatoid arthritis, lupus, MS), diabetes, and allergies?	True.
Which presents longer peptides: MHC class I or MHC class II?	MHC class II has a larger binding cleft which allows it to present longer peptides (13-24 amino acids), while MHC class I has a smaller binding cleft so presents shorter peptides (8-10 amino acids). MHC I often presents nonomers, whereas MHC II often presents 18-mers.
How does the binding of the T cell receptor complex to the MHC-antigen complex result in clonal expansion of the naive T cell in the immune response? What term describes this activation?	Intracellular signalling by the CD3 proteins of the T cell receptor complex, as well as by co-receptors, results in activation of the T cell. IL-2 is produced by the T cell while, simultaneously, the T cell also produces a high-affinity IL-2 receptor which is exported to the cell surface. The IL-2 binds to the receptor of the T cell that secreted it and the T cell clonally proliferates (so that the MHC molecules on its surface will be identical and specific to the antigen) - hence, the T cell 'auto-activates'.
Of the HLA A/B/C and HLA DP/DQ/DR genes, which encodes MHC I and which encodes MHC II?	MHC I is encoded by HLA A/B/C genes, while MHC II is encoded by HLA DP/DQ/DR genes.
Does MHC I or MHC II have two transmembrane regions?	MHC II has two transmembrane regions, one from its α chain and one from its β chain. Alternatively, MHC I has one transmembrane region from its α chain, and its β microglobulin is just a single protein.
Does the cytosolic or endocytic pathway result in an MHCI-antigen complex being exported to the cell membrane to present antigen to CD8+ T cells?	The cytosolic pathway. The endocytic pathway results in an MHCII-antigen complex being exported to the cell membrane to present antigen to CD4+ T cells.
What is the major difference between the cytosolic and endocytic pathways for the production of MHC to be exported to the cell surface to present antigen?	In the cytosolic pathway, endogenous antigen is transported to the rough endoplasmic reticulum where MHC is produced and combined with MHC I (as the endogenous antigen is from an intracellular pathogen/neoplastic antigen). However, in the endocytic pathway, MHC II is produced by the rough endoplasmic reticulum and combined after its transport towards the cell membrane in secretory vesicles, with exogenous antigen that has been endocytosed.
In the endoplasmic reticulum, MHC I that is being produced is highly unstable, both in its early α chain form (when it is stabilised by calnexin) and when its β2 microglobulin is added (when it is stabilised by calreticulum, tapasin and other chaperone proteins), so how is it stabilised enough to be exported to the cell membrane in order to present antigen to CD8+ T cells?	Binding of endogenous antigen peptides to MHC I molecule clefts stabilises the structures such that the chaperone proteins 'fall off' and are recycled.
What is the MHC class II invariant chain?	This is a chaperone protein which is bound to the MHC II binding cleft from its production in the endoplasmic reticulum to the binding of antigen in the cytoplasm, both to stabilise its structure and to stop it from binding antigen too soon (as early as MHC I). In the Golgi complex, the invariant chain is digested to a CLIP fragment which is displaced by antigen when the late endosome containing partially digested antigen binds with the secretory vesicle containing the MHC II.
List four similarities between the endocytic and cytosolic pathways for antigen presentation?	Both use MHC molecules to present antigen to T cells; both require stabilising chaperone proteins in the endoplasmic reticulum; the chaperones for both MHC I in the cytosolic pathway and MHC II in the endocytic pathway are recycled before exocytosis to the cell surface; and both are processed in the Golgi body and exocytosed to the cell surface in secretory vesicles.
List some differences between the cytosolic and endocytic pathways for antigen presentation?	The cytosolic pathway involves endogenous antigen whereas the endocytic pathway involves exogenous antigen; antigenic peptide is bound to MHC I while it is in the endoplasmic reticulum, whereas antigenic peptide is bound to MHC II while in the late endosome-vesicle fusion; MHC I has three different chaperone proteins for stabilisation whereas MHC II has one invariant chain; exogenous antigen requires the clathrin pathway for endocytosis whereas nothing of this sort is required for antigen in the cytosolic pathway; MHC II must have its binding cleft blocked with its invariant chain to stop it binding whereas MHC I binds freely; simple endocytosis is involved for capturing antigen in the endocytic pathway, whereas proteosomes, transport proteins and exocytic vesicles are required for the cytosolic pathway; and the cytosolic pathway uses proteosomes to break down antigen whereas the endocytic pathway uses enzymes and acid in lysosomes.

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T cell receptor-MHC interactions

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