this chapter talked about t-cell receptors and the ligand that they bind, MHC molecules. MHC's are surface molecules expressed on host cells that display peptide fragments derived from antigen. MHC's are differentiated by two classes: class 1 MHC's bind to intracellular peptide fragments, from antigen which has been degraded by proteosomes in the cytosol. class 2 MHC's bind to peptides in extracellular vescicles which have been degraded by lysosomes or acidification.
t cells are also divided into two families based on the type of antigen they are responding to. CD8 t cells respond to intracellular antigen (such as viral infection) and accordingly bind to MHC class 1 molecules, which trap intracellular antigen. CD4 t cells respond to extracellular antigen (such as bacterial infection) and therefore bind to MHC class 2 molecules. within CD4 t cells, TH1 cells stimulate macrophages to release cytokines and TH2 cells stimulate b cells to release antibodies.
the t cell receptor is similar in structure to one Fab arm of the b cell immunoglobulin, in that it is made out of two chains with 4 domains and an antigen binding site on the extended end. the diversity of the variable domain is also created in a similar way to the immunoglobulins in that it uses somatic recombination of varied gene segments. one main difference between t cell receptors and immunoglobulins is that while immunoglobulins are modified after contact with antigen, either to class switch to a different effector function or to enhance binding specificity for the antigen, t cell receptors remain the same.
MHC molecules, as mentioned above, bind to peptides in host cells and present them to t cells to provoke an immune response. whereas all host cells have class 1 MHC's, only professional antigen presenting cells have class 2 MHC's: dendritic cells, macrophages, and b-cells. although MHC's are binding a diverse array of peptide from antigen, the source of diversity of the binding site is much different than that of immunoglobulins or t cell receptors. instead of random rearrangement of gene segments, MHC binding sites achieve high diversity by the polymorphism present in the genes that encode them.
questions
1. what are the similarities between immunoglobulins and t cell receptors?
2. what are the two chains in a t cell receptor?
3. what are CDR's and how many does each t cell receptor have?
4. what is the context in which antigen binds to t cell receptors?
5. why are t cell receptors not further modified after encountering antigen, as immunoglobulins are?
6. what gene segments do the alpha and beta chain locuses contain?
7. where does t cell receptor gene rearrangment occur?
8. what is SCID?
9. what is Omenn syndrome?
10. what is the CD3 complex?
11. what are gamma-mu t-cells?
12. what type of t cell receptor do t cells that reside in epithelial tissue have?
13. what are the different subdivisions of t cells?
14. HIV exploits which receptor on t cells?
15. what are the divisions within MHC molecules and what type of T cells do they bind to?
16. describe the structure of MHC class 1 and class 2 molecules.
17. how does the structure of MHC molecules allow for simultaneous binding of t cell receptors and coreceptors?
18. compare the length of peptides pinned down by MHC class 1 and class 2's.
19. what are TAP's?
20. what are chaperones?
21. the MHC class I molecules cannot leave the endoplasmic reticulum unless..
22. how do MHC's relate to autoimmunity?
23. describe the intracellular path by which MHC class II molecules bind to peptides in extracellular vesicles.
24. what are the two functions of invariant chains?
25. what is HLA-DM and what does it do?
26. what is a common cell that lacks MHC class I molecules?
27. describe the difference between the body's expression of MHC class I and II molecules.
28. what are professional antigen presenting cells?
29. what effect does the cytokine IFN-gamma have on professional antigen presenting cells?
30. what is it that makes MHC's highly polymorphic?
31. what are the class 1 MHC isotypes?
32. what are the class 2 MHC isotypes?
33. what are anchor residues?
answers
1. t cell receptors are like the Fab portion of an immunoglobulin in that they are made up of two different chains and have a variable region on the outside. t cell receptors are also formed by somatic recombination of gene segments just like immunoglobulins as well.
2. TCR-alpha and TCR-beta.
3. complementarity determining regions, each chain has three; each t cell receptor has 6.
4. only via opposing cell surfaces when binding to antigen peptides presented by MHC's on the surface of other cell (as opposed to soluble immunoglobulins binding to antigen in solution).
5. because immunoglobulins act as effectors which need to increase their efficiency of binding to the particular antigen; whereas t cell receptors are simply receptors.
6. the alpha chain contains V and J gene segments and thus is analogous to the immunoglobulin's light chain whereas the beta chain contains V,J, and D, and is analogous to the heavy chain.
7. in the thymus
8. severe combined immunodeficiency disease, in which the RAG gene complex is dysfunctional, leading to absence of functional B and T (hence the "combined") cells.
9. immunodeficiency syndrome caused from a partially defective RAG gene.
10. the four invariant membrane proteins that t cell receptors associate with in the ER, which facilitate expression of the receptor on the cell surface.
11. a set of t cells that express t cell receptors with gamma-mu chains instead of alpha-beta chains.
12. mostly the gamma-mu t cell receptors.
13. CD4 and CD8 t cells, based on a specific glycoprotein present on the t cell's surface. CD4 t cells are cytotoxic, killing infected cells. CD8 t cells are further subdivided into TH1 cells, which activate macrophages, and TH2 cells, which stimulate antibody release from b cells.
14. the CD4 receptor.
15. MHC class 1 molecules bind intracellular antigens and therefore to the cytotoxic CD8 cells, and MHC class 2 molecules bind antigen in extracellular vescicles, therefore binding to CD4 helper cells.
16. MHC class 1 is made up of 4 extracellular units, 2 layers of 2 domains. the closest layer has one transmembrane alpha domain and a beta protein (which is not encoded by the MHC), while the outer layer has two alpha domains that make up the peptide binding site. MHC class 2 is made up of 4 extracellular units as well, where the first layer is made up of an alpha and beta domain, and the outer layer is made up of another alpha and beta domain.
17. the t cell receptor and peptide binds to the outer domains and the coreceptors bind to the inner layer.
18. the length is limited in class 1 MHC to about 9 amino acid long peptides, because both sides of the peptide are pinned down to the peptide binding pocket, whereas in class 2 MHC's the can extend beyond the pocket and can thus be longer.
19. TAP's are "transporters associated with antigen presentation" which transport peptides that result from antigen breakdown in proteosomes, into the ER to meet with MHC class 1 molecules.
20. chaperones are proteins that aid in the folding and the binding of peptides for MHC class 1 molecules.
21. they have bound a peptide.
22. in the absence of an infection, MHC's present peptides derived from the host rather than from antigens. if the t cells respond to these self antigens, this produces autoimmunity.
23. in this pathway, antigen is phagocytosed/endocytosed into phagosomes, which combine with lysosomes to form phagolysosomes, which degrade the antigen into peptides. the MHC class II molecules then travel to these vesicles and bind to peptide, and then are expressed on the cell surface.
24. invariant chains bind to MHC class II's in the ER, preventing them from binding to the peptides destined for class II MHC's. they also aid in transport to the extracellular vesicles which contain peptides that they will eventually bind to.
25. HLA-DM is the molecule that removes the CLIP (the last bit of the invariant chain that is not removed by proteases in the extracellular vesicles) from the MHC class II, allowing it to bind peptide.
26. erythrocytes.
27. all cells have MHC class I molecules and are thus under total surveillance via t cells for viral infection. only certain cells have MHC class II molecules, and are called professional antigen presenting cells.
28. macrophages, dendritic cells, b cells; can present peptide derived from extracellular vesicles to the CD4 T cells.
29. it upregulates the MHC class II molecules and therefore aids in response to infection or inflammation.
30. the presence of many alleles within the gene families that code for MHC's.
31. the class 1 MHC isotypes are HLA-A,B,C,E,F,G
32. HLA-DM, DO, DP, DQ, DR
33. residues on the peptide that have side chains that bind to pockets within the binding groove of MHC's
main ideas:
t cell receptor structure and synthesis
subdivisions of function among t cells
differences in MHC classes between:
structure of molecule
function
peptides bound
cells which express them
invariant chains
source of MHC polymorphism
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