T Cell Activation and Generation of Effector T Cells Flashcards
Where are the microbes that B lymphocytes target?
β extracellular
Where are the microbes that T lymphocytes target?
β intracellular
Describe T cell activation briefly?
β Generated in bone marrow and they undergo maturation in the thymus
β mature naive T cells are released from the thymus into the blood
β recirculate between blood and peripheral lymphoid orangs
β if they encounter antigens that they recognise lymphocyte activation,proliferation and differentiation occurs
How do naive mature T cells become mature?
β Ag recognition
β activation, proliferation and differentiation into effector T cells and memory T cells
What are T cells designed to fight?
β Intracellular bacteria
β viruses
β cancer cells
How do T cells recognise antigens?
β after processing and presentation
What do Ξ±Ξ² TCR recognise?
β peptides
What do Ξ³Ξ΄ T cells recognise?
β antigens that are not peptides
How do T cells recognise antigens?
β via their T cells receptor
What is the structure of Ξ±Ξ² TCR ?
β one alpha chain and one beta chain
What is the structure of a Ξ³Ξ΄TCR?
β one gamma and one delta chain
What is each chain made up of?
β 1 variable domain and one constant domain
What is the antigen binding site made up of?
β VΞ± and VΞ²
What domains are homologous in TCR and BCR?
β V and C domains
What T cells have Ξ±Ξ² TCR?
β CD4 and CD8 T cells
What T cells have Ξ³Ξ΄ TCR?
β all other T cells
What do MHC molecules display?
β peptides from processed Ag
What does MHC I present to and what is its structure ?
β CD8+ T cells
βcomposed of Ξ± and Ξ²2 microglobulin
What does MHC II present to and what is its structure?
βCD4+ T cells
βcomposed of Ξ± and Ξ² chain
What cells express MHC I?
β all nucleated cells
What cells express MHC II?
β APC
β dendritic cells, macrophages
What are human MHC molecules called?
β HLA (human leukocyte antigen)
What are the MHC I HLAs?
β HLA-A
β HLA-B
β HLA-C
What are the MHC II HLAs?
β HLA-DP
β HLA-DQ
β HLA-DR
What forms the peptide binding groove in MHC I?
β two alpha chains
What forms the peptide binding groove in MHC II?
β alpha 1 and beta 1 chain
What cells are the only ones capable of presenting to naive T cells?
β dendritic cells
What do macrophages present to?
β previously activated effector T cells
What do CD8+ T cells recognise?
β antigens displayed by nucleated cells
Where are dendritic cells found?
β mucosa
β skin
β tissues
What are dendritic cells in the skin called?
β Langerhans cells
What are the 5 functions of dendritic cells?
β Capture microbes β transport microbes from tissue to draining lymph nodes β process microbes into antigens βpresent antigens to naive T cells β activate naive T cells
What are the three signals dendritic cells use for naive T cell activation?
β TCR recognising antigen
β Co-stimulation
β Cytokine signals
Describe how naive T cells are activated by dendritic cells?
β the first signal is the TCR recognising the antigen and the peptide in combination with MHC
β it needs a second signal called co-stimulation
β this is done by the ligation of the co-stimulatory receptor CD28 (on the T cell) by the co-stimulatory molecules CD80/86 (on the APC)
β the third signal is via the cytokines
What do the cytokines secreted by the dendritic cell to activate the naive T cell depend on and what do they determine?
β The type of infection
β it determines what type of effector the activated T cells differentiate into
What happens if only the first signal occurs?
β no response
β anergy
β tolerance
What does infection do to the APCs?
β increases the antigen presenting functions and increases the expression of co-stimulatory molecules and of MHC
What cytokines does the APC need to produce to make a TH1 cell?
β IL-12
β IFN gamma
What do TH1 cells induce?
β macrophage co-operation
What do TH2 cells induce?
β B cell and eosinophil/mast cell co-operation
What are the 4 functions of macrophages?
β Phagocytose microbes
β Antigen presentation to effector CD4+ T cells
β activation of TH1 cells
β TH1 cells activate macrophages to kill ingested microbes
What cells can present to CD8+ T cells?
β all nucleated cells
What are CD8+ cells specialised to do?
β recognise viral antigens and proteins
β eliminate cells infected by viruses/ malignant cells
What can CD8+ recognise antigens from in addition to all nucleated cells?
β microbes that have been phagocytosed if the antigens escape from the phagosome into the cytosol
What antigens are presented to CD4+ T cells?
β exogenous antigens are taken up in cells, processed and presented by MHC II
What are the three things that can happen to exogenous pathogens?
β taken up by phagocytes
β eliminated via killing in phagocytes
β eliminated by antibodies (neutralisation, opsonisation and complement activation)
What cell types does CD4+ help?
β Macrophages (TH1)
β B cells (TH2)
Describe how a bacterial peptide is presented onto MHC II in 14 steps?
1)A macrophage takes up a bacteria into an endosome
2)The bacteria is broken down
3)The proteins from the bacteria are contained within the endosome and are fused with a lysosome
4)Enzymes cleave the proteins which produce peptides
5)MHC molecules are produced in the ER, if there is nothing to fill the peptide region then the molecule is unstable and MHC gets degraded
6)In the ER the newly generated MHC molecules are conjugated with the invariant chain that has a fragment that stabilises the groove
7)The complex of MHC and the invariant chain leaves the ER and into the golgi into an exocytic vesicle
8)While the vesicle is travelling to the surface it ends up in the late endo-lysosomal compartment where the peptides from the bacteria are
9)The invariant chain gets destroyed by the low pH of the lysosome except for one small fragment called CLIP which remains in the groove
10)The compartment expresses another molecule (HLA-DM) that is a class II MHC molecule, it is not involved in antigen presentation but in freeing the groove of the MHC to allow it to load the peptides.
11)The HLA-DM has a higher affinity for CLIP and it βstealsβ away from the MHC II
12)The MHC II has a free groove now that the bacterial peptide can enter in
13)If the MHC II cannot find a peptide it will be degraded
14If a bacterial peptide has entered then the MHC II will be stabilised and it will leave via a vesicle and is fused on the plasma membrane
What antigens are presented to CD8+ T cells?
β cytosolic antigens (viruses,mutated proteins in cancer cells)
Describe how viral proteins are presented on MHC I in 9 steps?
1) There is an infected APC or an epithelial cells (viruses can infect any nucleated cell)
2) There is a virus growing in the cytosol with proteins of the virus present in the cytosol
3) During a viral infection, cells develop proteasomes that are specialised in recognising viral proteins
4) They take up viral proteins and break them down into peptides
5) The peptides are imported into the ER via a transporter called TAP
6) MHC I is generated in the ER
7) The MHC I has a free grove so the peptides can fit
8) If the MHC I finds a peptide that fits in the groove, it is stabilised and it can leave, if it doesnβt find a peptide it gets degraded
9) If a peptide is found it leaves via an exocytic vesicle to the membrane and presents on the surface of the cell for recognition by CD8+
What are the three types of effector T cells?
β T helper cells
β Cytotoxic T lymphocytes
β Regulatory T cells
What are the 4 types of T helper cell and what are their functions?
β TH1 - help phagocytes kill ingested microbes β TH2 - help eosinophils/mast cells to kill helminths β TH17- role in defense against bacteria & fungi β TFH - help B cells class switch
What do Regulatory T cells express?
β CD4
β CD25
β FOXP3
What are the two cytokines that induce differentiation into TH1 and what kind of cells produce them?
β IL-12 and IFN gamma
β APC infected with bacteria
What is the main cytokine produced by TH1?
β IFN gamma
What are the 4 roles of TH1?
β MAIN :activate phagocytes and stimulates destruction of intracellular pathogens
β OTHER : stimulate production of IgG antibodies and phagocytosis of microbes
What are the cytokines that induce differentiation of TH2 and what kind of cells produce them?
β IL-4
β IL-25
β IL-33
β APC infected with helminths
What are the 3 cytokines produced by TH2?
β IL-4
β IL-5
β IL-13
What are the 4 main roles of TH2?
β help B cells produce IgE
β IgE opsonises helminths
β activates eosinophils & mast cells
β eosinophils & mast degranulation and killing of helminths
What disease is TH1 present in?
β autoimmunity
β chronic inflammation
What disease is TH2 present in?
β Allergy
What diseases is TH17 present in?
β autoimmunity
β inflammation
What diseases is TFH present in?
β autoimmunity
How do effector T cells leave the activation site?
β via blood
In what way do CD8+ T cells kill cells and why?
β antigen-specific
β contact- dependent so uninfected/healthy cells are not killed
What 2 cytolytic molecules do CD8+ T cells use?
β Perforin - forms pores and delivers granzymes
β granzymes A,B,C initiate apoptosis
What is CD8+ T cell killing mediated by?
β the death receptor pathway Fas/FasL
