Antigen Recognition by T Cells Flashcards
What is an antigen?
- a combo of ‘antibody’ and ‘generate’
- any molecule that can bind specifically to an antibody
- ie generate antibody responses
- proteins, carbohydrates, lipids capable of binding to B-cell receptors, T-cell receptors and/or innate immune receptors
- induce immune response
What is the epitope?
- adaptive immune rxns occur to specific epitopes (portions of antigen) as opposed to the entire antigen itself
- infection + vaccination usually induce polyclonal T- and B-cell responses
What is another term for MHC?
HLA
What are “professional” antigen-presenting cells?
- immune cells that can express high levels of MHC class II
- can efficiently induce T-cell responses
- macrophages, dendritic cells, B cells
- monocytes less so, but differentiate into macrophages
What are the roles of macrophages and dendritic cells and how do they differ (what are they each better at)?
- rare in peripheral blood - enriched in mucosal tissues
- highly phagocytic cells - induce strong T-cell responses + inflammation
- important for protection against TB
- macrophages better-equipped to kill pathogens (higher NO production)
- DCs better at migrating to lymph nodes (via CCR7) + presenting antigen to T-cells
- specialised but ultimately overlapping functions
What is the role of B-cells?
- highly abundant in blood + mucosal tissues
- receptor-mediated internalisation of antigens, as opposed to phagocytosis
- primary function to make antibody (plasma cell) - but still v good at presentation
- possibly main inducer of T-cell immune response to pathogens such as Neisseria meningitidis
Will T-cells recognise just any antigen?
No, the antigen must be processed in order to be recognised by T cells - cell surface peptides of Ag presented by cells that express MHC antigens
The following will not induce a T cell response:
- soluble native Ag
- cell surface native Ag
- soluble peptides of Ag
- cell surface peptides of Ag
What evidence suggests antigen-processing is a catabolic process?
- catabolism reduces antigens to peptides that can be recognised by T cells
- whereas native ovalbumin (antigen) cannot induce a T cell response to a fixed APC
- digested ovalbumin (antigen) CAN induce a T cell response
- showing importance of peptides binding to MHC on APC surface in order to induce T cell
What is the difference between exogenous and endogenous antigen processing?
- Exogenous - antigen uptaken from outside cell eg. extracellular bacteria (S. aureus, N. men.)
- Endogenous - antigen from inside cell eg. viruses (HIV, tumour antigens)
What processes + receptors are important for uptake of exogenous antigens?
- membrane Ig receptor mediated uptake
- phagocytosis
- pinocytosis
- complement receptor mediated phagocytosis
- Fc receptor mediated phagocytosis
Uptake mechanisms direct antigen into intracellular vesicles for exogenous antigen processing
Describe the mechanism/cellular pathway of uptake of exogenous antigens and how they are expressed on MHC class II
- exogenous protein internalised into early endosome
- exposed to proteases
- if it’s a bug - exposed to NO, low pH, reactive oxygen species to kill bug
- then early endosomes become late endosomes or “lysosomes”
- these are increasingly toxic (lower pH, stronger enzymes)
- this fuses with MHC Class II compartment (MIIC)
- meanwhile MHC class II exported from ER + joins MIIC
- invariant chain sits where antigen would be - helps to stabilise MHC
- enzymes also start to degrade invariant chain - leaves behind CLIP (class II associated invariant chain peptide)
- MHC recognises antigen -> high-affinity rxn displaces CLIP, CLIP degraded
- HLA-DM helps to shuffle loaded MHC to surface of cell
- MHC can then interact with TCR on CD4+ cell !! :)
What are cathepsins?
- proteases / enzymes that degrade proteins
- found in the endosomes / lysosomes
Describe the mechanism/cellular pathway for endogenous antigen processing and presentation of MHC class I
- peptide antigens prod in cytoplasm are physically separated from newly formed MHC class I
- peptides need access to the ER in order to be loaded onto MHC class I molecules
- cytosolic protein (viral protein) goes through proteosome
- chopped up into peptides
- TAP (transporter associated w antigen processing) shuttled peptides into ER
- peptides undergo further degradation in ER by amino-peptidases (ERAPs) + bind to MHC I
- MHC I transported to cell surface to interact w CD8 T cell
Antigens generated by endogenous + exogenous antigen processing activate different effector functions. How are exogenous pathogens eliminated?
by antibodies + phagocyte activation by T helper cells that use antigens generated by exogenous processing
How are endogenous pathogens eliminated?
killing of infected cells by CTL (cytotoxic T killer cells) that use antigens generated by endogenous processing
What about pathogens that don’t infect APCs? So if a virus only infects lung ciliated epithelial cells (eg. avian influenza), then how would you ever generate a good T-cell response against it?
- epithelial cells are not v good at activating the immune system
- APCs are best at inducing T-cell responses
- if the virus never infects an APC, would you never get good T-cell responses?
- the problem is overcome by antigen cross-presentation
What cells are primarily responsible for antigen cross-presentation?
Myeloid CD11c+CD8a+ dendritic cells
(CD8+ dendritic cells -> help induce CD8+ T cell response)
What is retrotranslocation, in terms of antigen cross-presentation?
- so you have both the CD8(endo) and CD4(exo) pathways
- each with their cytosolic proteins and then endosomal proteins
- retrotranslocation -> diversion of endosomal antigens to cytosol
- so endosomal proteins become cytosolic proteins, then can be presented to CD8+ cytotoxic killer cells
- even a dendritic cell this way that can’t be infected by a virus can still produce a really good immune response against that virus by cross-presentation
