Antigen Capture and Presentation Flashcards
How does the innate immune response innate the adaptive immune response?
- process and present antigen to T lymphocytes
2. Generation of surface molecules that function as costimulatory signals with antigen to active T and B lymphocytes
What are MHC/HLAs?
Antigen presenting molecules that allow immune system to distinguish between self and non-self.
Germline encoded, two halotypes from parents that are co-dominate allowing for more diversity
What are general structural features of Class I MHC/HLA?
Heterodimer of 2 proteins
Class I genes encoded by 3 seperate gene regions (A, B, and C)
- alpha chain encoded by MHC/HLA class locus, forms 3 domains (alpha 1, 2, and 3), membrane bound glycoprotein
- Beta2 micoglbulin, non MHC encoded, associates non covalently with the alpha 3
- peptide bond between alpha 1 and 2 (area of variability)
Closed ends in peptide binding groove= size limit
All alleles of Class I can expressed at the same time of each cell
What is the role of Class I MHC/HLAs?
Present CD8 cytotoxic T
Inhibitory receptor for NK Cells
What are the general structural feature of Class II MHC/HLA?
Encoded by HLA-D region
two proteins= alpha and b chain that are strongly associated via peptide forming binding groove NOT covalently linked
four globular domain structure just like class one
Open ends allow larger peptides to bind
All alleles of the alpha and beta expressed (3 alpha and 3 beta from mom and 3 alpha and beta from dad), can associate however they want –> diversity
What is the role of Class II MHC?
Presents antigen to CD4+ T
Where do you find Class I MHC?
All nucleated cells
Where do you find Class II MHC?
antigen presenting cells= macrophages, dendritic, and B-lymphocytes
What are the key features of HLA peptide binding?
Slow on rate and very slow off rate so can actually present antigen, saturable low affinity interaction
Only one peptide binds to a molecule at a time even though is able to bind multiple different ones (pockets specific for size, shape, and hydrophobicity, not AA sequence)
How is MHC restricted?
CD4+ binds Class II MHC beta chain
CD8+ binds Class I MHC alpha 3 domain
everything equals 8
What are the 3 main types of APCs?
Dendritic cells, macrophages, B lymphocytes
What is the distinct cell marker expression, costimulators and function of Dendritic Cells?
Professional APCs because constitutive expression of MHC II, increased by IFN-gamma
Costimulators constitutive, increased by TLR ligands, IFN-gamma, and T cells
APC for native T cells
What is the distinct cell marker expression, costimulators and function of macrophages?
low or negative expression of Class II MHC (inducible by IFN-gamma)
low expression of costimulators, induced by IFN-gamma, TLR ligands, and T cells, get from NKs
APC for CD4+ effector T cells
What is the distinct cell marker expression, costimulators and function of B lymphocytes?
Class II MHC constitutive, increased by cytokines (IL-4)
Costimulators induced by T cells and antigen receptor cross linking during immune synapse
APC for CD4+ helper T cells in humoral response
What is the pathway of antigens captured in the periphery in comparison to the blood?
Periphery= filter by lymph and lymphoid tissues
Blood= filtered by spleen (macrophages)
What happens when dendritic cells are activated?
Once activated lose adhesive markers and upregulate CCR7 for binding to lymph endothelium
Increase expression of MHC and CD80 (costim.)
Travel to lymph tissue and mature during migration before presenting antigen to naive T
What is the Class II MHC pathway for processing?
Vesicle binds with lysosome in cell making peptides
At same time HLA alpha and beta chains being made in ER and held together by invariant chain which keeps peptide from binding the groove
The molecule goes to the golgi via exocytotic vesicle. binds with lysosome that has degraded peptides.
Lysosome enzymes degrade invariant leaving CLIP
HLA-DM exchanges CLIP for peptides for Class II MHC and displays on cell surface
What is the Class I MHC pathway for processing?
Proteins produced in cytosol are degraded via proteasome
In interior of ER Class I alpha chain made, tapasin holds molecule there as TAP feeds peptides from cytosol into ER and complex assembled
Transported to the golgi and then exocytoced on to cell surface for CD8+ cytotoxic
Why is CLIP so important?
MHC I protein complexes are being made at the same time in ER don’t want intra cellular thing presented to Class II
What is cross presentation?
Permits the presentation of exogenous antigens, which are normally presented by MHC II on the surface of dendritic cells, to also be presented through the MHC I pathway
- use MHC 1 to remain unaffected and MHCII to signal adaptive immune response to T cells
What is ankylosing spondylitis? What HLA allele is it associated with?
inflammation of the spine
HLA-B27
What is Rheumatic fever? What HLA allele is associated with it
Generation of antibodies against strep that cross-react with cardiac tissue
HLA-DR4
What is a cause of renal cell carcinoma?
Class I antigen processing defect= TAP (transporter) down regulated
What causes Bare Lymphocyte Syndrome?
TAP protein non functional so peptides cannot enter the ER and bind to Class I molecule –> cannot leave ER and are bare leading to chronic viral infections
What cause Bare Lymphocyte Syndrome Class II?
Inherited defect in CIITA (transactivator induced by IFNgamma) leading to deficiency in HLA class II and on function T lymphocytes (decreased humoral responses because reduced antigen presentation to mature CD4+)
