8. Antigen Processing and Presentation II (Snippets)

Question 1

what are the three signals to activate naive lymphocytes to specific effector?

Answer 1

1. antigen receptor (TCR-peptide/MHC)
2. costimulation (CD28/B7)
3. Cytokines (lead to specific effector functions)

Question 2

central dovma of adaptive immunity?

Answer 2

Phenotypic changes to the DC = ‘loss of DC adhesiveness” and means that the chemokine receptors change when the DC becomes stimulated and moves out of the epithelium. They become lymp node-attracted at this point, which is based on the changes to the type of chemokine receptors expressed. Important for stimulation of both CD4 and CD8 cells

phenotypic changes to the DC:

• increase class II and class I
• upregulate B7
• change chemokine receptors
• go from a phagocytic phenotype to a processing machine

Question 3

Th1 cells do what?

Answer 3

macrophage activation: destruction of phagocytosed microbe

Question 4

Th-all, esp TFH cells do what? (T-follicular helper)

Answer 4

B cell antibody secretion: antibody binding to microbe

Question 5

CD8 cells do what?

Answer 5

kill antigen-expressing infected cells

Question 6

dendritic cells do what?

Answer 6

APCs only

Question 7

macrophages do what?

Answer 7

APCs when activated by T cells or PAMPA; otherwise they clean things up

Question 8

B cells do what?

Answer 8

present BCR-binding antigens to antigen-specific T cells

Question 9

when do DCs express Class II MHC?

Answer 9

constitutive, but increases as mature

Question 10

when do macrophages express Class II MHC?

Answer 10

low; induced by IFN-gamma

Question 11

when do B cells express Class II MHC?

Answer 11

constitutively, augmented by cytokines

Question 12

costimulation (eg B7) is inducible how in DCs?

Answer 12

by PAMPS, pro-inflamm cytokines, and CD40-40L

Question 13

costimulation (eg B7) is inducible how in macrophages?

Answer 13

by PAMPs, proinflamm cytokines, CD40-40L

Question 14

costimulation (eg B7) is inducible how in B cells?

Answer 14

by T cells (CD40-40L) and antigen

Question 15

what is the principle function of DCs?

Answer 15

initiation of naive T cell responses to protein (CD4 and CD8)

Question 16

what is the principle function of macrophages?

Answer 16

induction and effector phases of CMI

Question 17

what is the principle function of B cells?

Answer 17

present antigen to antigen-specific CD4 helpers

Question 18

naive and some memory T cells require cosimulation (eg B7) - what about effector T cells?

Answer 18

do not require costimulation, only the ag/MHC recognition

Question 19

plasmacytoid DC?

Answer 19

part of the innate immune system making large amounts of Type I IFNs upon activation (hopefully can take care of pathogen without adaptive immunity)

Question 20

MHC restriction?

Answer 20

TCR recognizes the peptide/MHC complex

Question 21

T cells respond vigorously to APC bearing non-self MHC alleles, in the so called _____ response (the bane of transplantation surgeons)

Answer 21

allogenic/allo response

Question 22

Class I and Class II genes are very polymorphic - each allele will bind what?

Answer 22

a particular set of peptides, which in turn will activate different clones of antigen-specific T cells

Question 23

what part of the Class I MHC is MHC encoded?

Answer 23

only H chain

Question 24

peptides that bind class I MHCs are generated where?

Answer 24

the cytosol

Question 25

Class I molecs are upregulated during infection via what?

Answer 25

cytokines, exp gamma IFN

Question 26

class II molecs are expressed by which cells?

Answer 26

B cells, DCs, macrophages, and thymic epithelium

Question 27

peptides that bind class II MHC are generated where?

Answer 27

lysosomes

Question 28

Class II MHC are upregulated during infection via what?

Answer 28

cytokines, esp gamma IFN

Question 29

Treg cells do what?

Answer 29

dampen immune response

Question 30

Th2 cells do what?

Answer 30

involved in defense of epithelia/mucosae, against extracellular parasites

Question 31

Th17 cells do what?

Answer 31

stimulate phagocytosis of extracellular pathogens

Question 32

superantigens produced by some bacteria and viruses are what?

Answer 32

proteins that bind to the MHC Class II and to the framework regoins of the TCRV regions - thus act as glue for T cells, regardless of their antigen specificity, and APC, regardless of the peptides displayed in the class II grooves.

SUCH NON-ANTIGEN-SPECIFIC ACTIVATION OF T CELLS RESULTS IN OVERPRODUCTION OF CYTOKINES THAT MAY PREVENT EFFECTIVE ANTIGEN-SPECIFIC IMMUNE RESPONSES TO COMMENSE

pathogen essentially attempts to deviate a specific immune reponse

Question 33

class I molecs are expressed by almost all cells of the body - this makes biological sense why?

Answer 33

any cell of the body can become infected with viruses and thus must be sacrificed to prevent viral spread

Question 34

what are DRiPs?

Answer 34

defective ribosomal products - misfolded proteins. They make up 40% of proteins biosynthesized at any time and are degraded by the proteosome….the short peptides are then transported across ER membrane by TAPs where peptides then bind to class I molecs

Question 35

tapasin?

Answer 35

a chaperone that holds class I with TAP (required for efficient binding of the peptides to class I within the ER lumen)

Question 36

upon treatment of APCs with gamma IFN, what happens to the machinery of MHC Class I molecules?

Answer 36

transcription of class I genes and TAP and proteosome genes is upregulated - leading to an increased expression of class I molecs bearing foreign peptides

Question 37

changes of the proteosome following infection and cell stimulation by gamma IFN?

Answer 37

three of the proteasome components (of 14) are beta components and are only found among those induced by infection. They change hte specificity of the proteolytic cleavages such that the peptides produced have more of a tendency to bind to class I molecs

Question 38

what is the “regulatory cap”

Answer 38

PA28 or 11S, induced upon infection and binds to the core 20S proteasome - the cap is believed to augment peptide-cleavage and thereby increase the efficiency of antigen processin gand presentation

Question 39

mature, cell-surface Class I molecs are thought of as trimolecular complexes consisting of what?

Answer 39

class I heavy chain, Beta2 microglobulin, and peptide

Question 40

proteins taken up form the outside can be processed and presented as peptides on class I molecules - a phenomenon called “cross priming” or “cross-presentation. This is required for responses to tumors and for the initiation of responses of viruses. Why is this so important?

Answer 40

naive CD8 cells require two signal (MHC/peptide and costim) when they are first activated (DCs are the most active cells in this process - macrophages don’t have this machinery = CD8+DC)

Question 41

the lymphocyte precursor frequency for a particular foreign antigen is 1/100,000 to 1/1,000,000. However, the frequency for foreign MHC alleles is much higher (1/100 - 1/1,000), which is the bane of transplantation surgeons. Why is it so high?

Answer 41

the anchor residues on peptides are specific for each MHC allele - thus allogenic MHC alleles (alleles not expressed by self) will SELECT DIFFERENT SETS OF PEPTIDES FROM SELF PROTEINS than the ones selected by self MHC alleles. therefore our own T cells will not be tolerant of these foreign MHC/peptide complexes and make very strong immune responses (true for both class I and class II molecs)

Question 42

why are grafts rejected even when the MHC is shared by the donor and recipient (like siblings)?

Answer 42

minor histocompatibility antigens (polymorphisms in other genes in the genome…when peptides from these polymorphic molecs associate with ‘self’ MHC, the complexes are recognized as foreign, just like a peptide froma virus or tumor would be recognized - the precursor freqeuncy for these self MHC/foreign peptides is low, but nonetheless will result in a T cell response)

Question 43

can pathogens poison the proteasome?

Answer 43

no

Question 44

ways that viruses poison the MHC I/MHC II pathway?

Answer 44

• block the peptide’s entry into ER (HSV 1 blocks peptide binding to TAP)
• retention of MHC Class I in ER (adenovirus competitively inhibits tapasin, HCMV blocks tapasin function)
• degradation of MHC Class I (HCMV transports some newly synth MHC Class I molecs into cytosol)
• Binds MHC Class I at cell surface (Murine CMV interferes with recognition by cytotoxic lymphocytes by an unknown mechanism)

Question 45

MHC Class I tetramer technology

Answer 45

Each TCR is on the cell surface as monovalent, so using a single labeled MHC-peptide complex to bind T cells is not possible. But tethering 4 of the same MHC peptide complexes together provides enough AVIDITY (will stick to the cell longer) so that the T cells can bind these “tetramers” and the tetramers can be coupled to a flourochrome for visualization via FACS

especially useful for the tracking of viral-specific T cells during an immune response (or for monitoring tumor antigen-specific cytotoxic T cells or helper cells)

Question 46

the most common deficiency for class I is a mutation in what?

Answer 46

TAP; loss of peptide supply to the ER constipates class I molecules in this organelle and they never get to the surface! Pts have no Class I at the surface and no CD8 T cells either

Question 47

the most common form of class II deficiency is what?

Answer 47

absence of certain TFs specific for class II gene promoters - these pts lack CD4 cells because of a failure of positive selection by thymic class II molecs

Question 48

certain MHC alleles are associated with autoimmunity or excessive inflammation - eg?

Answer 48

Coeliac disease in which a particular class II allele (DQ2 specific allele or deficiency) is associated with presentation of dietary (gliadin) peptide

Question 49

knowledge of ______ for particular MHC alleles allows us to predict the peptides from bacterial/viral proteins that can bind to those alleles.

Answer 49

anchor residues

Question 50

In the absence of infection, what do MHC molecules bind?

Answer 50

self peptides (MHC molecs require peptides to be expressed at the cell surface)

T cells become tolerant of these peptide/MHC complexes during thymus differentiation