Flashcards in 8. Antigen Processing and Presentation II (Snippets) Deck (50):
what are the three signals to activate naive lymphocytes to specific effector?
1. antigen receptor (TCR-peptide/MHC)
2. costimulation (CD28/B7)
3. Cytokines (lead to specific effector functions)
central dovma of adaptive immunity?
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
Th1 cells do what?
macrophage activation: destruction of phagocytosed microbe
Th-all, esp TFH cells do what? (T-follicular helper)
B cell antibody secretion: antibody binding to microbe
CD8 cells do what?
kill antigen-expressing infected cells
dendritic cells do what?
macrophages do what?
APCs when activated by T cells or PAMPA; otherwise they clean things up
B cells do what?
present BCR-binding antigens to antigen-specific T cells
when do DCs express Class II MHC?
constitutive, but increases as mature
when do macrophages express Class II MHC?
low; induced by IFN-gamma
when do B cells express Class II MHC?
constitutively, augmented by cytokines
costimulation (eg B7) is inducible how in DCs?
by PAMPS, pro-inflamm cytokines, and CD40-40L
costimulation (eg B7) is inducible how in macrophages?
by PAMPs, proinflamm cytokines, CD40-40L
costimulation (eg B7) is inducible how in B cells?
by T cells (CD40-40L) and antigen
what is the principle function of DCs?
initiation of naive T cell responses to protein (CD4 and CD8)
what is the principle function of macrophages?
induction and effector phases of CMI
what is the principle function of B cells?
present antigen to antigen-specific CD4 helpers
naive and some memory T cells require cosimulation (eg B7) - what about effector T cells?
do not require costimulation, only the ag/MHC recognition
part of the innate immune system making large amounts of Type I IFNs upon activation (hopefully can take care of pathogen without adaptive immunity)
TCR recognizes the peptide/MHC complex
T cells respond vigorously to APC bearing non-self MHC alleles, in the so called _____ response (the bane of transplantation surgeons)
Class I and Class II genes are very polymorphic - each allele will bind what?
a particular set of peptides, which in turn will activate different clones of antigen-specific T cells
what part of the Class I MHC is MHC encoded?
only H chain
peptides that bind class I MHCs are generated where?
Class I molecs are upregulated during infection via what?
cytokines, exp gamma IFN
class II molecs are expressed by which cells?
B cells, DCs, macrophages, and thymic epithelium
peptides that bind class II MHC are generated where?
Class II MHC are upregulated during infection via what?
cytokines, esp gamma IFN
Treg cells do what?
dampen immune response
Th2 cells do what?
involved in defense of epithelia/mucosae, against extracellular parasites
Th17 cells do what?
stimulate phagocytosis of extracellular pathogens
superantigens produced by some bacteria and viruses are what?
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
class I molecs are expressed by almost all cells of the body - this makes biological sense why?
any cell of the body can become infected with viruses and thus must be sacrificed to prevent viral spread
what are DRiPs?
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
a chaperone that holds class I with TAP (required for efficient binding of the peptides to class I within the ER lumen)
upon treatment of APCs with gamma IFN, what happens to the machinery of MHC Class I molecules?
transcription of class I genes and TAP and proteosome genes is upregulated - leading to an increased expression of class I molecs bearing foreign peptides
changes of the proteosome following infection and cell stimulation by gamma IFN?
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
what is the "regulatory cap"
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
mature, cell-surface Class I molecs are thought of as trimolecular complexes consisting of what?
class I heavy chain, Beta2 microglobulin, and peptide
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?
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)
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?
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)
why are grafts rejected even when the MHC is shared by the donor and recipient (like siblings)?
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)
can pathogens poison the proteasome?
ways that viruses poison the MHC I/MHC II pathway?
- 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)
MHC Class I tetramer technology
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)
the most common deficiency for class I is a mutation in what?
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
the most common form of class II deficiency is what?
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
certain MHC alleles are associated with autoimmunity or excessive inflammation - eg?
Coeliac disease in which a particular class II allele (DQ2 specific allele or deficiency) is associated with presentation of dietary (gliadin) peptide
knowledge of ______ for particular MHC alleles allows us to predict the peptides from bacterial/viral proteins that can bind to those alleles.