T Cell Activation Flashcards
What are the functions of Th and Tc cells?
- Th coordinate immune response
- Tc identifies and kills infected cells
How do Th and Tc cells function via TCR?
- resembles a membrane bound antibody Fab fragment
- 2 transmembrane glycoprotein chains - alpha & beta
- form in a similar way to the B cell receptor
- diversity: multiple copies of variable gene segments rearranged in different combinations
Describe the 3 signals involved with T cells
- Signal 1: TCR interaction with specific antigen on MHC
- Signal 2: co-stimulatory signals
- Signal 3: not required but commonly delivered, cytokines that effect T cell differentiation
Describe antigen presenting cells in the naive immune response
- dendritic cells critical in activation of T cells - both CD4 and CD8
- dendritic cells differentiate from circulating monocytes
Describe APCs in active immune response
- macrophages and B cells also important APCs presenting to Th cells via MHC class II
Describe dendritic cells in APC
- Immature DCs present in epithelial surfaces - engulf antigen
- migrate via afferent lymphatics to lymph node
- reside in paracortex where they present antigen to naive T cells via MHC
Describe how dendritic cells present to CD8+ cells
via antigen cross presentation - presentation of exogenous antigens on MHC class I
Describe why there is diversity in MHC genes
- T cells can only recognise antigen in context of self (MHC)
- binding of antigen to MHC molecules critical in T cell activation
- therefore diversity in MHC genes
Describe the 3 types of diversity in MHC genes
- polygenic
- polymorphic
- combination of polygenic and polymorphic
Describe polygenic diversity in MHC genes
- several different genes for class I and II
- each individual will present 3 sets of class I molecules and 4 sets of class II
Describe polymorphic diversity in MHC genes
- many alleles for each gene
- MHC one of the most polymorphic gene known
Describe the variation between MHC allotypes
concentrated in:
- peptide binding groove affecting peptide recognition
- alpha helices forming walls affecting TCR recognition
Describe how polymorphism is created
- point mutations
- gene conservation - chunks of one gene copied into structure of another
- pseudogenes can be a source of genetic material bringing about gene conservation
Describe Class Ia and Class II MHC
- each MHC molecule binds a limited repertoire of peptides influencing adaptive immune responses
- heterozygotes express more alleles and a wider range of peptide binding
- overdominant selection - heterozygous advantage
- evidence for influence on sexual selection
Describe how MHC can influence sexual selection
- detection of MHC via olfaction due to MHC pheromones
Describe MHC Signal I in dogs
- due to small gene pools - some pedigree breeds have limited intra-breed variability in MHC genes - increased levels of MHC homozygosity
- DLA alleles associated with resistance/susceptibility to poor response to rabies vaccine in Rottweilers
Describe MHC in cattle
BoLA alleles associated with resistance/susceptibility to:
- ticks
- mastitis
- foot and mouth disease
Describe MHC in horses
ELA alleles associated with resistance/susceptibility to:
- allergic response to Culicoides bites
- sarcoid tumours
Describe Signal I
- TCR interacts with MHC
- MHC class II interacts with CD4+/Th
- MHC class I interacts with CD8/Tc
- specificity dependant on CD8 and CD4
Describe the Signal I function on CD4 and CD8 molecules
- stabilise/strengthen TCR/MHC interaction
- transduce signal to T cell
- affinity of MHC-peptide complexes and TCRs is weak
- needs CD4/CD8 to reinforce binding
Describe co-stimulation of Signal II
- CD40 receptor on APC
- CD154 receptor on T cell
- activatory signal for both APC and T cell
- CD28 on T cell surface
Describe CD28 on T cell surface
- interacts with CD80 or CD86 on APC
- activates T cell
- without CD80/CD86 interaction - no activation
- important in preventing immune responses
- turns T cell into an anergic T cell - unable to create a response
Describe CD8+ T cell activation
- tend to require higher levels of co-stimulation
- role of activated CD4+ also in activation of CD8+
- release of IL-2 from CD4+ T cell one way
Describe the ways T cells can respond to antigen after activation
- effector T cells
- no/far lower requirement for co-stimulation
- change adhesion receptors to change circulation
Describe what proliferating T cells express more and its effects
- express more CTLA-4 (CD152)
- CD80-86 interaction with CTLA-4 leads to inhibitory signals
Describe the PD-1 receptor and its role in inhibiting T cell activation
- present on T cells after activation
- binding of PD-1 to either PD-L1 or PD-L2
- PD-L upreg on macrophages/NK/B cells after IFNү stimulation
- critical in cancer
- cancer cells manipulate PD-1/PD-L1 downreg inflammation
- antibodies created against PD-L1 block interaction
Describe the antibodies created against the PD-L1 block interaction
- increase stimulation
- more pro-inflammatory cytokines (IL-2 and IFNү)
In which species is PD-1 conserved?
- cats
- dogs
- cattle
- horses
