L15: T cell selection/tolerance - periphery Flashcards
Peripheral tolerance (4)
- Lack of costimulation: T cell anergy or deletion during priming
- Regulatory T cells: natural Tregs (thymus), inducible Tregs (periphery), characterised by Foxp3 expression, production of TGF-b, IL-10, cell contact
- Activation induced cell death (AICD): activated T cells can undergo apoptosis during the immune response
- Cytokine deviation e.g. Th1 vs Th2 vs Th17
T cell selection/function dictation parameters in periphery (3)
- Density of peptide/MHC
- Peptide structure
- Immunodominance
Avidity
Sum of total interactions which help the immunological synapse transmit a signal.
Peptide/MHC density and Avidity
- Low avidity T cell - high amounts of peptides
2. Low concentration of peptides - high avidity
Functional avidity
Way of measuring avidity by observing the final effector function
T Cell functional avidity
The sensitivity of a T cell effector response to changes in peptide/MHC density, dictated by:
- Affinity of the TCR
- Number of TCRs
- Accessory molecules (number and affinity)
- Intracellular signalling events
High and low avidity CTL
- High avidity CTL are better at viral clearance than low avidity CTL: able to recognise low levels of peptide, clear virus and limit spread.
- Low avidity CTL recognise overexpressed self-antigen in tumours but ignore lower levels of the same self-antigen in normal tissue
Altered peptide ligands (APL)
Closely related peptides in which one or more AA are different from the WT peptide sequence
- Agonist APL = induces a T cell response that is quantitatively and qualitatively similar to WT peptide
- Weak agonist APL = induce the same responses as WT peptide, but require high doses of peptide
- Superagonist APL = induce the same responses as WT peptide, but at lower doses of peptide
- Partial agonist APL = induce a subet of responses seen to WT peptide (conformational change so only part of signalling molecule occurs)
- Antagonist APL = inhibits T cell activation induced by WT when both peptides are present on the same APC
Immunodominance
Focusing of the immune response on a limited number of peptide determinants derived from complex proteins
Immunodominance - Epitopes (3)
- Immunodominant epitope = epitope to which the majority of the T cell response is directed
- Subdominant epitope = epitopes which elicit T cell responses as peptides but are weakly immunogenic in context of intact protein
- Cryptic epitope = epitopes which elicit T cell responses as peptides but are not immunogenic in the intact protein under normal circumstances
Factors affecting immunodominance (4)
- Intracellular processing of peptide
- Peptide binding to MHC
- Available T cell repertoire
- T cell competition
Intracellular processing of peptide (5)
- Flanking sequences at either end of the peptides can contribute to the efficiency of proteases
- Cytokine induced changes in the proteasome
- Rate of protein synthesis and degradation e.g. unstable proteins
- Cellular location of the protein e.g. nuclear vs.cytoplasmic
- Pathogen interference with antigen processing or protein synthesis
Peptide binding to MHC (2)
- High affinity binding result in immunodominant peptide
2. Peptide binding to MHC dictated by anchor residues
Available T cell repertoire (2)
- Positive and negative thymic selection may alter the repertoire such that immunodominant determinants are favoured
- Number of T cell precursors and their ability to proliferate will dictate immunodominance
T cell competition
- Response of CD8 T cells to an immunodominant epitope may suppress the response to subdominant epitopes, resulting from:
a) reduction of antigen load leading to suboptimal levels of other epitopes
b) competition at level of APC
c) systemic suppression of subdominant responses
