T cells Flashcards
lecture 8
action of CD8 t cells
secrete cytokines eg IFNgamma to inhibiti viral replication.
macrophage activation
kill virally infected cells and tumour cells.
action of CD4 t cells
help naiive B cells, help CD8 t cells, activate macrophages, cytokine secretion
TCR structure
simlilar to an antibody Fab fragment and variability is generated in the same way.
- an alpha and a beta chain, each with one constant region and one variable region. together the two form the TCR
TCR vs BCR
1 - monovalent
2 - mebrane bound, no secreted counterpart
3 - no somatic hypermutation
4 - solely for antigen recognition
TCR recombination
VDJ recombinaion of the beta chain and its expression with a surrogate alpha chain in the CD4/8 double negative T cells.
- then CD4 and 8 are expressed and the alpha chain undergoes VJ rearrangement.
- complete TCR expressed and then CD4/8 selection takes place.
what mediates the recombinaiton of TCR
RAG1 and 2 recombinases - same as BCR.
the mRNA may contain unrearanged segments that have to be spliced out to give the funcitonal mRNA
where is most of the variation in the TCR
in the CDR3
what are T cells selected for and why
1 - successful beta chain rearrangemen
2 - positive selection - ensures theyll be useful by being able to recognise self MHC
3 - negative selection - prevent autoimmunity by removing autoreactive cells.
only 1-2% of double negative T cells survive selection
describe positive selection
newly arranged TCRs are tested against self peptide/MHC complexes expressed on cortical epithelial cells.
- TCRs with moderate affinity recieve a positive signal and continue maturation. lack of signal causes death by neglect.
- cells that survive will be CD4 single positive if selected against MHC2/peptide, or CD8 single positive if selected against MHC1/peptide
describe negative selection
those who bind the MHC/prptide complexes ith high affinity undergo apoptosis.
- this doesnt remove those that are autoreactive to combinations not ofund in the thymus though, for those the process of peripheral tolerance is needed
progress of T cels through the thymus
precursors enter the outer sub-capsular region of the thymus and progress towardst he centre of the lobe (the medulla) via the cortex.
where does the positive selection take place
in the cortex with the cortical epithelial cells
- thymocytes here continually rearrange their alpha chain segments to give multiple opportunities for positive selection
- lack of positive selection is the major cause of thymocyte death,
what cells mediate negative selection
dendritic cells and macrophages trigger it.
2 signal hypothesis
proposes that signal 1 is delivered by TCR engagement and co-stimulatory molecules deliver signal 2
costimulatory molecules for T cells
CD28 on the T cell interacts with B7.1 (CD80) and B7.2(CD86) on the APC
- also CD40L on the T cell interacts with CD40
expression of the constimulatory molecules is a defining feature of professional antigen presenting cells.
DC activation?
DC take up antigen, are activated by their innate PRRs, then increase MHC 2 synth and begin to express B7.1 and B7.2
then migrate to the draining lymph nodes and present antigen to the T cells.
how do T cells go into lymph nodes
via high endothelial venules
what happens if a naiive cd4 T cell encounters its antigen on a DC
cease migration, binding of costim induces the naiive T cell to proliferate and differentiate into an expanded population of armed effector T cells
how are naiive B cells activated
bind antigen via its surface Ig and internalise it (signal 1).
- process and present it on MHC2. an activated cd4 t helper which was activated by the same antigen on the DCs will then interact with the presenting complex.
- CD28 and CD40L on the T cell bind B7 and CD40 on the B cell (b cell signal 2) and causes mutual activation of the two cell types.
whats the funciton of follicular dendritic cells
hold intact unprocessed antigen on their surface as immune ocmplexes. only present in B cell follicles and enable the activated B cells to form germinal centres - where B cells proliferate and undergo both somatic hypermutation and isotype switching. during this process affinity maturation takes place
what are thymus independent antigens
those that can stimulate naiive B cells without the need for B/T cell interaction. they are typically microbial products with repeating epitopes that crosslink membrane Ig to induce B cell proliferation
when CD8 t cells leave the thymus they are destined to become cytotoxic T cells, CD4 cells however can become one of several types. what are the 2 most imp
Th1 or Th2 T cells.depending on the nature of the anitgenic challenge and the cytokines present during proliferation.
describe Th1 T cells
produce cytokines to support inflam and cell mediated responses
- activate macrophages, NK cells, CTLs and are important vs intracellular pathogens.
describe Th2 t cells
activate mainly B cells and immune responses dependent on antibodies
role of innate system on defining TH1/2 differentiation.
because the differentaition betweenthe 2 subsets occurs so early in immune responses, the cytokines produced by the cells of the innate system (DCs, macrophages, NK cells) play a vital role in focusing the immune response.
- the abundance of antigen, the MHC/peptide concentration and T cell receptor affinity also influence the response.
- abundant antigen and high affinity TCR interaction stimulates Th1 responses
- low peptide abundance or weak affinity TCR interaction stimulates Th2 responses.
- once the bias is established, it is self reinforcing.
Th1 pathway
cellmediated immunity, cytokines such as IFNgamma (from Th1 and NK cells) activate macrophages and inhibit TH2. the macrophages produce IL-12 to promote NK and Th1
Th2 pathway
IL-4 from mast cells stimulates TH2 and inhibits Th1.
- TH2 cell produces IL-4 to reinforce and stimulate B cell growth (with IL-6 too) and inhibit TH1.
- TH2 also secrete il-10 to inhibit the macrophages and their IL-12 produciton.
one big interwoven cycle.
Ig production: IL-4 IgG1 IL-5 = IgA IL-4 = IgE also stimulates the effector cells - mast cells IL4 and eosinophils IL5
