immunology: erica's cytokine chart

made by the undisputed master of chartmaking in our class, erica zelfand

immunology: parham's the immune system chapter 6- t cell mediated immunity

this chapter talked about the activation and actions of the three different types of t cells: CD8 t cells, CD4 TH1 cells, and CD4 TH2 cells.

naive t cells are formed in the thymus and are constantly in circulation and are activated only when they encounter antigen presenting cells (APC's) in the lymph. there are three "professional" antigen presenting cells- dendritic cells, macrophages, and b cells. out of these three, dendritic cells are most involved in activating t cells, because they migrate from peripheral tissues, where the infection occurs, into the lymph nodes where they can encounter naive t cells- whereas macrophages stay in the infected tissues to combat the infection.

activating a t cell requires several factors to be in place: first the expression of cell adhesion molecules such as LFA's on the surface of the t cells and APC's will transiently bind the two together, allowing the t cell receptors to have a chance to bind to the MHC:peptide complex on the APC. to be fully activated, the t cell receptor needs to be specific for that particular MHC:peptide, and co-stimulation also needs to occur. costimulation is the expression of the CD80 or CD86 ligand on the APC surface in response to binding of common microbial constituents such as lipoproteinsaccharide. CD80/86 binds to CD28 on the t cell, which causes the release of the cytokine IL-2, which causes proliferation and differentiation of the t cell.

thus, costimulation acts as a confirmation of the presence of an infection. if no costimulation occurs, this generally means that the t cell is being presented with a self-antigen. this leads to no IL-2 being secreted, and the t cell goes into the state of "anergy", where the t cell receptors are actually less receptive to the (self) antigen next time it encounters it.

t cells can then differentiate into cytotoxic CD8 t cells, which migrate to the site of infection and release cytokines and cytotoxins into the virus infected cells. when the CD8 cells are activated in the lymph tissue, they form "lytic granules" which are then released in close proximity to the infected cells. these granules contain perforin, granulysin, and granzymes- the first two perforate the cell membrane and allow granzymes to enter the infected cell, which activates proteases and enzymes which trigger apoptosis.

t cells can also differentiate into CD4 TH1 cells, which are involved in macrophage activation. these cells also migrate to the site of infection in peripheral tissues. they secrete a number of cytokines such as IFN-gamma, TNF-alpha, IL-2, IL-3, GMCSF, the chemokine CXCL2, and the ligand CD40, which have various effects on the macrophage. IL-3 and GMCSF cause increased macrophage production in the bone marrow. IL-2 causes the TH1 cells to proliferate. TNF-alpha facilitate diapedesis of macrophages into sites of infection. but perhaps most importantly, the cytokine IFN-gamma and the CD40 ligand on TH1 cells stimulate macrophages to increase microbicidal activity, such as increased fusion of phagosomes with lysosomes, or creating more reactive oxygen species. this helps the fight against pathogens which reside within the macrophages themselves.

finally, t cells can differentiate into CD4 TH2 cells, which are involved in activating b cells. t cells might come into contact with a dendritic cell in the lymph tissue and then differentiate into a TH2 cell; in contrast to the other t cells which migrate to the infected tissues, the TH2 cell remains in the lymph tissue to await an encounter with the circulating b cells. in order to activate a b cell, it needs to recognize the MHC:peptide from the same antigen that it is specific for. this causes the t cell to express the CD40 ligand and secrete cytokines IL4,5 and 6, which cause b cell proliferation and differentiation into plasma cells.

questions
1. why are dendritic cells better suited to activate naive t-cells in the peripheral lymph tissues compared to macrophages?
2. for any given infection, a naive t cell specific for the pathogen will represent 1 in ... of the total population of circulation t cells.
3. how long does it take for naive t cells to differentiate into effector t cells?
4. how do t cells move from circulation into the lymph tissues?
5. what is an LFA and how is it related to the maturation of a t lymphocyte?
6. what is costimulation and what molecules are required in this process?
7. what is CTLA4 and what does it do?

8. what are the three types of professional antigen producing cells and where do they reside in the lymph node?
9. describe the maturation of a dendritic cell.
10. what do macrophages do in the lymph node?
11. how are macrophages activated to professional APC status?
12. how does listeria subvert the body's immune defenses?
13. describe how b cells act as APC's.
14. what are adjuvants?

15. what is ZAP-70?
16. what does the tyrosine kinase pathway ultimately induce?
17. how is IL-2 produced?
18. what effect does IL-2 have on t cells?
19. what is the state of anergy?

20. what is Th1 and Th2 activation called?
21. describe the development of a bias of Th1 vs. Th2 cells.
22. which is the only APC cell that can stimulate CD8 activation and why?
23. what are the three ways in which CD8 cells can be activated?

24. describe the difference in costimulation requirements for effector CD8 and CD4 cells.
25. what are lytic granules?
26. describe the formation and release of lytic granules by cytotoxic CD8 cells.
27. what is the cytokine that CD8 secretes and what does it do?
28. what are the cytotoxins that CD8 cells release and what do they do?
29. what are Fas ligands and how do CD8 cells use them?

30. what is macrophage activation?
31. what are the cytokines required for macrophage activation?
32. how do CD-8 t cells also contribute to macrophage activation?
33. how do TH2 cells inhibit macrophage activation?
34. what are the different cytokines produced by TH1 cells and how do they contribute to macrophage activation?

35. describe the activation of B cells via TH2 cells.
36. what are the cytokines involved in activation of B cells? what effect do they have?


answers
1. because dendritic cells are migratory cells which travel from the site of infection to the lymph tissues, whereas macrophages reside in the tissues to combat infection.
2. 1 in 106.
3. a few days.
4. via cell adhesion molecules and chemokines.
5. LFA is lymphocyte functioning associated antigen, an integrin on the surface of the t cells which aids in the transient connection to dendritic cells, so that the t cell receptors might bind to a MHC/peptide complex, thereby beginning the maturation process.
6. in order for the t cell to differentiate, two things must occur: the MHC/peptide has to bind to the t cell receptor, and the CD28 receptor on the t cell must bind to either the CD86 or CD80 ligand on the dendritic cell. this is called co-stimulation.
7. it binds to CD86 or CD80 20 times as strongly as CD28 and acts as an antagonist, inactivating t cells.

8. dendritic cells are in the cortex, macrophages are throughout the cortex and medulla, b cells are in the germinal centers.
9. once dendritic cells bind to antigens in the peripheral tissues they migrate to the cortex of lymph nodes and undergo several changes: they display costimulatory molecules on their surface, secrete chemokines which attract naive t cells, and increase their cell adhesion molecules to facilitate the transient connections described in question 5.
10. they phagocytose circulating pathogens - for the purposes of stimulating t cells as well as preventing the infection from reaching into the blood and becoming systemic. they also kill lymphocytes.
11. through binding of one of their germline encoded surface receptors: mannose receptor, scavenger receptor, complement receptors, toll like receptors.
12. once phagocytosed by macrophages, it resides in the cytosol instead of being destroyed in a phagolysosome.
13. b cells bind antigen via their surface immunoglobulins, which are then endocytosed and presented on class II MHC's. costimulatory molecules are expressed in response to binding of certain microbial components (such as LPS).
14. adjuvants are bacterial components that are used to stimulate costimulatory molecules in APC's.

15. ZAP-70 is a tyrosine kinase that is activated when the t cell receptor binds to a MHC/peptide complex, which is involved in initiating the intracellular signalling pathway.
16. the production of transcription factors which initiate the profileration and differentiation of t cells, and also the upregulation of cytokine production, such as IL-2.
17. IL-2 is upregulated when a t cell binds to both MHC/peptide as well as costimulatory molecule. IL-2 high affinity receptors are also upregulated upon t cell activation.
18. IL-2 induces proliferation of the antigen specific t cells.
19. anergy is when a t cell does not produce IL-2 and therefore cannot proliferate. this occurs when a naive t cell binds to self antigen (which therefore does not produce co-stimulation)

20. Th1 helper cells activate macrophage's microbicial activity and thus is called cell mediated immunity. Th2 activates b cells secretion of antibodies and thus is referred to as humoral immunity.
21. once Th1 or Th2 cells begin proliferating they suppress the other type.
22. dendritic cell, because they are the only APC that can provide sufficient costimulation.
23. dendritic cells can activate via costimulation, CD4 cells can secrete cytokines which stimulate APC's to express costimulatory molecules, and CD4 cells can also secrete IL-2 which binds to IL-2 receptors on CD8 cells, thereby activating them.

24. when CD8 and CD4 t cells proliferate and become effector cells, they can be stimulated to their effector functions without the need for costimulation by the CD80 or CD86 which is found only on professional APC's. this means that cytotoxic CD8 cells can destroy all infected cells it encounters and CD4 can better activate b cells in the lymph tissues.
25. modified lysosomes in CD8 t cells that contain cytotoxins.
26. lytic granules are formed in CD8 cells in response to activation by antigen in the lymph tissues. the CD8 cells then migrate to the site of infection and release the lytic granules upon binding to the antigen/MHC complex of infected cells. when the cell begins to die, the CD8 cell releases, forms new lytic granules, and attaches to another infected cell to repeat the process.
27. IFN-gamma, which upregulates the expression of MHC I, inhibits viral DNA replication, and activates nearby macrophages.
28. perforin and granulysin make pores in the cell membrane through which granzymes can enter, which then activate nucleases and enzymes that lead to apoptosis.
29. Fas ligands are expressed on cytotoxic CD8 t cells, which bind to the Fas molecules on infected cells, triggering apoptosis (a secondary route, although a primary route for disposing of old lymphocytes).

30. macrophage activation is the activation by CD4 TH1 cells whereby macrophage's antimicrobial activities are increased; phagosome fusion with lysosome is increased, microbicial molecules are produced, and antigen presentating to t cells is increased.
31. TH1 cells secrete IFN-gamma, TNF-alpha, and express the CD-40 ligand, all of which activate the macrophage.
32. CD-8 secretes IFN-gamma, which contributes to macrophage activation.
33. by the cytokines TGF-alpha, IL-4, IL-10, IL-13, which inhibit macrophage activation.
34. IL-2 promotes proliferation of t cells, IL-3 and GMCSF promote macrophage differentiation in the bone marrow, TNF-alpha and beta contribute to macrophage diapedesis into the site of infection, and CCL2 acts as a chemokine to guide the phagocytes to the infected area.

35. infected dendritic cells travel to the t cell areas of peripheral lymph tissues and activate naive t cells into TH2 helper cells. circulating b cells then come into contact with these TH2 cells and become activated.
36. IL-4, IL-5, IL-6 and CD40 ligand, which causes proliferation of b cells and differentiation into plasma cells.

immunology: parham's the immune system chapter 3- antigen recognition by t lymphocytes

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