Immuno exam 1 - Ag presentation Flashcards
How are lymphocytes activated?
Microbe taken up by APC at site of infection → APC enters lymph circulation, and into lymph node
*Naive T & B cells enter lymph node from circulation
Describe Ag presentation
Antigen presentation is central to development of immune response
Processes by which MHC-antigen interacts with TH or Tc
- Bridges antigen recognition to initiation of full-blown immune response
- Enables T cell-mediated killing, or augments antibody production by B cells
- Is context dependent allowing deployment of appropriate immune responses under different conditions
- Is modulated by co-stimulatory molecules
What is the result of antigen recognition without presentation
Tolerance
Name and describe the 3 APCs
Dendritic cells – most efficient for initial T cell activation (priming)
Macrophages – must be activated by phagocytoses before presenting antigens
B cells – for secondary immune response
*But not limited to them… all nucleated cells can present endogenous antigens in association with MHC I molecules
What is the meant by pathway 1 and pathway 2?
Pathway 1: Exogenous antigens into the cell, small peptide antigens generated & presented to TH cells together with MHC II molecule
Pathway 2: Endogenous antigens digested to small peptides & presented to CD8+ T cells
What is antigen processing?
antigens digested & placed on cell surface with correct MHC molecules
Describe the Cytosolic Pathway: Endoegenous Antigens
Proteins to be degraded link to ubiquitin (a small protein)
Degradation of ubiquitin-protein complex within central channel of proteasome
Peptides generated are transported into lumen of RER by Transporters associated with Antigen Processing (TAPs)
Newly synthesized MHCI binds to antigen peptide
Antigen-MHCI complex released & transported to cell surface
Extracellular antigens presented by macrophages or B lymphocytes to CD4+ helper T cells, which activate macrophages or B cells & eliminate the antigen
Describe the Endocytic pathway: exogenous antigens
Endocytic pathway: exogenous antigens
Antigens internalized by enodsomes, first digested there & then in lysomoses
MHCII molecules produced at RER & associated with invariant chain protein (Ii) preventing their binding to endogenous antigens
Class II-Ii complex move into endocytic compartments
Ii digested to short fragment MHCII-associated Invariant chain Peptide (CLIP)
HLA-DM triggers exchange of CLIP & antigen peptide
HLA-DO blocks active of HLA-DM
*CD8+ cytotoxic T cell
Cytosolic antigens presented by nucleated cells to CD8+ CTLs which kill antigen-expressing cells
What is MHC class 1?
MHC class I – polymorphic a chain noncovalently attached to nonpolymorphic β2 microglobulin; a chain is glycoslylated; extracellular portion of HLA-B27
What is MHC class 2?
Class II - polymorphic a chain noncovalently attached to polymorphic β chain; both chains are glycoslylated; extracellular portion of HLA-DR1
What are the 3 key roles of MHC?
Essential for antigen presentation to T cells
T cells constantly survey for foreign antigens
Self MHC + foreign Ag = T cell response
Self MHC + self Ag = no T cell response
Expression can be induced on almost every nucleated cell in the body
Viruses can infect any nucleated cell, MHCI function to alert the CD8+ T cells
MHC expression tells immune system that cell is a self cell
Key factor in determining tissue matching for transplant donors & receptors
Describe MHC geners (HLA)
Highly polymorphic – hundreds of alleles in humans with 1013 combinations
…why difficult to find transplant donors (even among 1st degree relatives)
Concomitantly expressed – set of alleles on chromosome=MHC haplotype
MHC hapoltypes can influence….
How an individual responds to certain pathogens
Susceptibility to certain diseases
Transplant success
What are 4 characteristics of MHC-peptide interactions?
MHC has broad specificity for peptides (many different peptides can bind within the MHC binding cleft)
Peptides associated with MHC have a slow on & slow off rate
MHC molecules do not discriminate from self & foreign peptides
MHC haplotype determines which peptides bind & how peptides bind
Describe MHC restiiction
Allows T cells to recognize foreign Ag on APC surface and to distinguish self & non self
In thymus (where T cells mature) T cells…
Are specific for foreign Ag+ MHC (positive selection)
Bind with low avidity to self peptide-MHC complexes survive
TCRs that bind with high avidity die (negative selection)
Prevents destruction of self tissue (autoimmunity)
Describe the immunological synapse
- MHC-peptide complex binds to TCR
o CD4 interacts with MHCII on APC & TCR on T cell to strengthen interaction
o CD8 interacts with MHCI on target cell & TCR on T cells - Co-stimulatory molecule B7 on APC binds to T cell ligand CD28
- Adhesion molecule ICAM-1 on APC binds to T cell ligand LFA-1
What is the temporal order of multiple ligand-receptor interactions at the immunological synapse?
Multiple ligand-receptor interactions
Temporal order of interactions:
Non-specific, reversible binding though adhesion molecules
Antigen-MHC-TCR binding provides specific interaction & results in prolonged cell-cell contact (Ag-specific activation)
Costimulation generates a second signal that is important for the fate of cell
Describe CD8 cell MHC restriction
CD8+ T cells are MHCI restricted & recognize cytosolic proteins
Describe CD4 cell MHC restriction
CD4+ T cells are MHCII restricted & recognize extracellular and intravesicular pathogens
What is the relationship b/t CD3 and TCR
CD3 and ζ are noncovalently associated to TCR
Expression of TCR CD3 and ζ chain are required for antigen recognition & signaling
TCR recognizes Ag, CD3 and ζ signal
Describe the effects of co-stimulatory molecules on T-cells
Antigen recognition by lymphocytes provide signal 1 for activation of lymphocytes
Molecules induced on host cells during innate immune responses to microbes provide signal 2
T cell will not be activated without them (anergy – “T cells will not respond”)
T cell will not be stimulated without antigen-TCR interaction (no effect)
Co-reception of both signals activate T cells
At termination of response, CTLA-4 replaces CD28 & downregulates T cell function
Describe the 2 different B-cell receptors
CD28 – before T cell activation
CTLA4 – at termination of immune response (“shuts T cell down”)
Can competitively inhibit CD28 binding
When bound to B7, will actively block signal from the TCR and from CD28
How doe bacterial product effect MHC expression?
Bacterial products stimulate the expression of MHC, adhesion molecules, and co-stimulatory molecules in APCs
These signals provide T cells with ‘context’ information that determine the modality of their responses (tolerance, TH1 or TH2 response)
Describe T cell activation following Ag presentation
Activation of tyrosine kinases associated with TCR/CD4(8) complex and phosphorylated cytoplasmic tails of the clustered receptors
Activation of kinase cascade follows & activation of transcription factors
Induction of IL-2 and IL-2R
Cell division after IL-2 ligation to IL-2R
