T-cells Flashcards
a) Overview of CD8 cytotoxic T cells
b) Overview of CD4 T helper cells
c) Main things to know about T cells (clinical impotance)
a) TCR binds to MHC class I. Activation causes cytokine release (eg IFNγ), inhibition of viral replication, macrophage activation, killing of virus infected cells (with cytotoxins), and killing of tumour cells
b) TCR binds to MHC class II. Activation causes help to naive B cells, macrophage activation, help for CD8 T cells, cytokine secretion
c) i) Severe combinded immunodeficiency (SCID) is caused by a genetic failure to devlop T cells. Inherited immunodeficiencies are known as primary immunodeficiencies or inborn errors of immunology, and there are ~400 known such genetic diseases ii) Acquired immunodeficiency (AIDS) is caused by HIV-mediated killing of CD4+ T cells. Other causes of acquired immunodeficiency are chemotherapy, blood cancers, and aging
a) Comparing TCR and antibody Fab fragments
b) Diversity of TCR
a) TCR has a variable (Vα and Vβ) domain, as does the Fab fragment (VL and VH). Also both have a constant region, TCR has Cα and Cβ, Fab fragment has CL and CH1. Both also have a disulphide bridge. However, the TCR is monovalent, membrane bound and doesn’t have a secreted counterpart (unlike BCR), doesn’t undergo somatic hypermutation, and is solely used for antigen recognition and isn’t linked to effector function.
b) (See image). RAG1 and RAG2 catalyse DNA recombination. The TCRβ VDJ genes are recombined first, followed by TCRα VJ genes (no D in α). T cells that have rearranged both TCRβ and TCRα genes successfully will express both CD4 and CD8. Total diversity of TCR is around 1x10^18, whereas immunoglobulin is 5x10^13 (because TCRs have greater junctional diversity)
a) T cell developmet and selection
b) Positive and negative selection of T cells and where this occurs
c) Where do mature T cells go?
a) T cell precursors travel from the bone marrow to be developed and selected in the thymus. Initially, T cells express both CD8 and CD4. The TCR will bind to a self peptide and either MHC class I or MHC class II on thymic epithelial cells. CD8+ T cells are selected for by MHCI, and CD4+ T cells are selected for by MHCII. Single-positive thymocytes are produced.
b) Occurs in the thymus. The affinity of a particular TCR for MHC/peptide is what determines selection. Clones with a low affinity fail selection and die by neglect. Clones with an intermediate affinity are positively selected for and will survive. Positive selection is done by cortical epithelial cells in the thymus cortex. Clones with a high affinity are negatively selected for and will be deleted. Negative selection is done by dendritoc cells, macrophades and other cells in the thymus medulla. Only ~2% of T cells are positively selected.
c) Mature T cells leave the thymus and travel to secondary lymphoid tissues (lymph nodes, spleen, GALT)
a) How does the TCR associate at the plasma membrane
b) Outline of TCR signalling and what can target these
a) (see image) The TCR needs to transduce signals into the cell, and cannot achieve this α and β. Associates with CD3ε,γ and ζ chains (coreceptors).
b) (see image). Upon antigen and MHC binding, a nearby Lck phosphorylates the tyrosines in CD3ζ. Zap-70 binds to the phosphotyrosines. Zap-70 then phosphorylates the nearby LAT. LAT recruits PLCγ (activate Ca2+ signalling pathways), and Grb2 and SOS (activate Ras and MAPK pathways). Cyclosporin is a drug frequently prescribed to organ transplant patients, it acts on the signalling pathway following PCLγ recruitment to inhibit gene transcription in the T cell so it doesn’t reject the new organ. Rapamycin is another drug used, and this acts on the signalling pathway following Grb2 and SOS recruitment.
Cytotoxic T cells interacting with targets
TCR will bind to peptide and MHCI on infected cell. T cell FASL will bind to infected cell FAS, which stimulates apoptosis of the infected cell. The T cell also secretes IFNγ which enhances the internal killing capacity of the infected cell. T cell also secretes Perforin and granzymes to lyse the infected cell.
Naive CD8 T cells cannot kill. They acquire this ability after activation when they start to express perforin and Granzyme B.
a) Signals required to activate T cells
b) Costimulatory signals between T (helper) cells and B cells
a) Requires two signals from the antigen presenting cell to activate the T cell. The TCR must bind to the MHC. CD28 on T cell must bind to B7 on the APC. This activates the T cell, and it will then express CD40L (used in costimulation)
b) The B cell takes up an antigen, processses it, and presents a peptide to the T cell (with matching MHC). The T cell is either activated by the B cell, or by another APC (described above). The T cell CD40L will bind to B cell CD40. The T cell secretes Il-4 and IL-21, which acts on the B cell to produce immunoglobin with an increased affinity for the antibody (somatic hypermutaion). T cells are also fully activated
a) Cytokine signalling for T (helper) cell differentiation
b) Th cell subsets (function, inducing cytokines, what cytokines they secrete)
a) First two signals - TCR binding to MHCII (initial T cell activation), and CD28 binding to B7 (T cell IL-2 production and clonal expansion). Third signal is secretion of cytokines from the APC, which causes differentialtion of the CD4 T cell.
b) Th1 - intracellular bacteria and viruses. Induced by IFNγ and IL-12. Secretes IFNγ
Th2 - extracellular parasites. Induced by IL-4. Secretes IL-4, IL-5, IL-13
Th17 - inflammation, extracellular bacteria. Induced by TGFβ, IL-6 and IL-23. Secretes IL-17 and IL-22
Tfh - B cell activation. Induced by IL-6. Secretes IL-21
Treg - regulate T cell activity. Induced by TGFβ and IL-2 (produced by all activated T cells). Secretes TGFβ and IL-10
How T cell subsets antagonise eachother
See image
