Immune Cell Interactions Flashcards
Describe the BCR and Ig alpha/beta complex.
- structure: membrane immunoglobulin, associates with Ig alpha/beta complex
- function: receptor-mediated internalization of antigen
Describe the TCR and CD3 complex.
- Structure
- TCR: alpha and beta subunits
- associates with CD3 complex
- Function
- interacts with MHC to recongize antigens
- CD3 acts as signal transducing subunit
What are the surface molecules that interact with MHC?
CD4, CD8
Define CAMs.
- Cellular Adhesion Molecules
- facilitate T cell adhesion
- augment signaling thru TCR
What are the Ig Superfamily of CAMs?
- structure based on Ig fold
- ICAM-1, ICAM-2, CD2, CD4, CD8
What are the Integrin Family of CAMs?
- heterodimers of alpha and beta chains
- LFA-1, MAC01, p150, p95
What are the Selectin Family of CAMs?
- extracellular portion is lectin domain
- binds to carbohydrate ligands, facilitate interactions between leukocytes and endithelium
- L-selectin, P-selectin, E-selectin
What are the Vascular Addressins CAMs?
- molecules w/ carbohydrate ligands recongized by L-Selectin
- CD34, GlyCAM-1
How does signaling between T Cells and APCs work?
- multiple interactions of CAM pairs
-
LFA-1 (integrin) on T cell interacts with ICAM-1 on APC
- signal is weak unless TCR also connects with MHC II + peptide on APC -or- chemokine binds to T cell
- integrin switched to high affinity state, T cell and APC interaction produces strong signaling
-
CD2 on T cell interacts with LFA-3 on APC
- promotes cell adhesion
- augments signal thru TCR
How does signalling between naive T cells and HEVs work?
- L-selectin on naive T cell interacts with sulfated sialyl-Lewisx motif on GlgCAM-1 and **CD34 **molecules of the HEV cell surface
- initiates rolling of naive T cell along endothelium so it can enter blood
What are the T Cell co-stimulatory molecules?
CD28 (positive) CTLA-4 (negative)
Describe the naive T Cell co-stimulatory mechanism.
- naive T cells require TCR/CD3 activation and a second, co-stimulatory CD28 signal to be activated
- **CD28 **on T cell interacts with B7 on professional APC
Describe the negative co-stimulatory mechanism.
- CTLA-4 on naive T cell binds to B7 on APCs
- outcompetes CD28, modulates T cell immune response
SUMMARY REVIEW: What are the T cell surface molecules responsible for antigen recognition?
TCR
SUMMARY REVIEW: What are the T cell surface molecules responsible for signal transduction?
CD3, CD4/CD8, CD2
Co-stimulation: CTLA-4, CD28
SUMMARY REVIEW: What are the T cell surface molecules responsible for adhesion?
LFA-1, L-selectin, CD2
Describe the B Cell co-stimulatory mechanism.
- B cell and T cell interact for antigen presentation
- B cell: MHC, B7
- T cell: TCR, CD28
- CD40L on T cell is expressed
- **CD40 **on B cell interacts with CD40L
- B cell proliferation
Describe the immunological synapse and SMACs.
- point of interaction between T cell and APC
-
c-SMAC: center of cluster
- T cell: TCR/CD3
- APC: MHC/Ag
-
p-SMAC: border of cluster
- T cell: LFA-1
- APC: ICAM-1
- formation initiates T cell signaling
Name and define the methods of action for cytokines. Examples?
- autocrine: cytokine acts on secreting cell
- ex. Il-2 during T cell activation
- paracrine: cytokine acts on neighboring cells
- ex. chemokine recruitment of leukocytes to site of inflammation
- endocrine: cytokine acts systemically
- ex. IL-1, IL-6, TNF-alpha in septic shock
What is the function of IL-2?
helps to activate naive T cells
Describe the IL-2 receptor and its regulation.
- part of common gamma chain family of receptors
- on naive T cells, expressed as form w/ only beta & gamma chains
- when secreted IL-2 binds, alpha chain of IL-2R binds with beta & gamma increases affinity of IL-2R
- IL-2: IL-2R binding signals T cell proliferation
What is the process for neutrophil extravasation to a site of infection?
- rolling: selectin on endothelium binds to carbohydrate ligand on neutrophil
- activation: chemokine binds to GCPR on neutrophil to activate **integrin **
- firm adhesion, transmigration: **integrin **on neutrolphil binds to ICAM on endothelium
What is LAD? What’s the molecular basis?
- Leukocyte adhesion deficiency
- caused by beta-integrin gene mutation, neutrophils can’t get out of blood stream
- suffer from bacterial and fungal infections
What is the function of MHC (HLA)?
when bound to peptide, they interact with TCRs
Does MHC bind to anything other than TCR?
Yes, ex. NK cell receptors. ONLY T cells recognize peptide in MHC
Where is Class I MHC found?
all nucleated cells (not RBCs)
Where is Class II MHC found?
restricted to professional APCs (DCs, B cells, macs)
What are the genes on the Class I MHC locus?
HLA-A, HLA-B, HLA-C
What are the genes on the Class II MHC locus?
HLA-DR, HLA-DP, HLA-DQ
What is the patterns of inheritance for MHC genes?
co-dominant: both alleles of each gene (one from each parent) are expressed and are functional
Define MHC gene polymorphism.
- many known alleles for each MHC gene locus
- polymorphisms occur in regions of MHC that contact the peptide and the TCR
What is the structure of Class I MHC?
alpha heavy chain
beta2 light chain (not on MHC locus)
peptide groove: closed on the ends, only holds short peptides
What is the structure of Class II MHC?
alpha and beta chains
groove for peptide: open on both ends, can hold short and long peptides
Where do the peptides associated with MHC come from?
- cytosolic (endogenous): host cell structural proteins, viral pathogens
- MHC Class I
- extracellular (exogenous): host serum proteins, bacterial pathogen proteins
- MHC Class II
Describe the endogenous pathway of MHC Class I antigen processing and presentaiton.
- production of proteins in cytosol
- proteolytic degradation of ubiquitinated proteins
- transport of peptides from cytosol to ER via TAP
- peptide- class I MHC complexes form in ER
- complex becomes exocytotic vessicle and gets expressed on membrane surface
Describe the exogenous pathway of MHC Class II antigen processing and presentaiton.
- extracellular proteins taken into APC cytoplasm and processed in endolysosome
- Class II MHC are synthesized in ER
- Class II MHC + Invariant Chain (Ii)
- Class II MHC-Ii fuses with endosome-lysosome containing antigen peptide
- Vessicle binds with CLIP that digests Ii
- Vessicle moves to cell surface so MHC II + peptide can be expressed
What is the function of invariant chain (Ii)?
blocks peptide binding site of MHC II while in ER so it cannot bind with other peptides (like those going into MHC I)
What are there 2 types of MHC/ antigen processing pathways?
- MHC I: important for intracellular pathogens, all cells are vulnerable to such infections
- MHC II: important for extracellular pathogens which can be readily accessed by phagocytosis
What determines peptide binding specificity of MHC?
- binding specificity is determined by size and shape of pockets in peptide-binding groove of MHC molecule
- different MHC alleles bind certain types of peptides
- peptide-binding pockets of MHC alleles bind to unique or chemically similar AA side chains (anchor residues)
How do TCRs recognize MHC?
- TCR recognizes specific combinations of MHC and peptide
- peptide residues not buried in MHC groove serve as binding sites for TCR
How do CD8 and CD4 recongize MHC?
- bind to non-polymorphic regions of MHC I and II
What is MHC restriction?
- a given TCR will only recognize a specific MHC molecules in complex w/ a unique (or a few similar) peptides
What is the clinical relevance of MHC polymorphism?
- rejection of tissue transplants
- basis for need to “cross-match” donor and recipient
- autoimmune diseases
- HLA-typing is the most useful test in definitive diagnosis of many autoimmune diseases
