effector T cells

dont forget to review the diagrams from the ppt

where do cytotoxic T cells come from?

CD8 T cells → recognize peptide:MHC-I complexes → differentiate into cytotoxic T cells

where do helper T cells and induced regulatory T cells come from?

CD4 T cells → recognize peptide:MHC-II complexes → differentiate into helper T cells (T_H) and induced regulatory T cells (iTreg)

where do cytokines come from and what do they do?

come from DCs and other innate immune cells

they induce differentiation of naive CD4 cells down distinct effector pathways

what determines which cytokines are produced?

conditions like the type of pathogen encountered determines which cytokines are produced by innate sensor cells - influences the type of effector cell created

what are the two types of regulatory T cells?

1. natural Treg cells (commit to regulatory pathway in thymus during development)

2. induced Treg cells (differentiate from CD4 T cells due to particular environmental conditions

what is the major site of helper T 17 cells and iTreg cell deployment?

mucosal tissue, particularly the intestine, which hosts lots of normal microbiota

why do you need and developmental balance between helper T 17 cells and iTreg cells?

its necessary to prevent unwanted immune response against normal microbiota while retaining the capacity to mount an immune response if the barrier is breached 

how is the developmental balance between helper T 17 cells and iTreg cells regulated?

regulated by the production of a vitamin A metabolite: all-trans retinoic acid (at-RA) and IL-6 by specialized mucosal DCs

resident DCs at homeostasis

the DCs present antigens that produce at-RA and induce differentiation of iTreg effector cells to supress inflammation

what happens when antigens are presented in the context of TLR signals as a result of infection?

at-RA production is suppressed in favour of IL-6 → development of helper T effector cells and inflammation is favoured

do effector T cells need co-stimulators?

no. when an effector T cell encounters its specific antigen, it can perform its function without co stimulation 

what do effector T cell loose?

effector T cells loose expression of L-selectins and stop recirculating through lymph nodes 

what do effector T cells express?

effector T cells epress ligands for P- and E- selectins and integrins, which allow them to enter tissues at the site of inflammation 

how is the supramolecular activation complex (SMAC) or the immunological synapse formed?

peptide:MHC recognition by effector T cells causes clustering of TCR and its associated co-receptors at the site of the cell to form SMAC or the immunological synapse

what do immunological synapses do?

they regulate signalling and direct the release of effector molecules

what are the two zones of the immunological synapse?

1. central zone (cSMAC): contains signalling proteins associated with TCR and co-receptors

2. peripheral zone (pSMAC): contains adhesion molecules (LFA-1) and cytoskeletal protein talin 

what happens to TCRs in the cSMAC?

TCRs are endocytosed and undergo ubiquitin-mediated degradation

what are TCR microclusters in the pSMAC for?

they are the site for active signalling necessary for T cell activation 

what does TCR signalling do for the effector T cells?

TCR signalling results in the reorientation of the secretary apparatus of the effector cell

ensures the release of effector molecules at the site of contact with the target cell

what is the process for releasing effector molecules at the cite of target cell contact?

local reorganization of the actin cytoskeleton at the site of contact → reorientation of microtubule-organizing center  and golgi apparatus 

what does cytoskeleton reorientation focus?

focuses exocytosis of the preformed cytotoxic granules in the cytotoxic effector cells, and the newly formed effector molecules at the site of contact with the target cell

how do cytotoxic T cells induce target cell death?

by apoptosis

what are the two general pathways of apoptosis?

extrinsic pathway and intrinsic (or mitochondrial pathway)

how does the extrinsic pathway of apoptosis work?

mediated by the activation of death receptors by extracellular ligands. CTLs express membrane-bound FasL, TNFα, or LTα, which bind death receptors on target cells to induce apoptosis

how does the intrinsic/mitochondrial apoptosis pathway work?

induced in response to noxious stimuli. CTL release the contents of their cytotoxic granules at the site of cell to cell contact to induce apoptosis in the target cells

how are apoptotic cells disposed of?

they are ingested by phagocytic cells and are completely digested without causing local inflammation 

apoptosis is an immunologically quiet process

what are cytotoxic granules?

they are modified lysosomes containing cytotoxic effector proteins

conditions within the granules prevent the action of cytotoxic effector proteins until their release 

what are the three classes of cytotoxic effector proteins?

1. perforin

2. granzymes

3. granulysin

cytotoxic effector proteins: perforin class

cause perforation of the target cell membrane to allow entry of other contents of cytotoxic granules. perforin can cause direct damage to the target cell

cytotoxic effector proteins: granzymes

induce apoptosis in the target cell by directly activating caspases and by causing release cytochrom c from mitochondria 

cytotoxic effector proteins: granulysin

can induce apoptosis of target cell at high concentrations

what is proteoglacan serglycin?

present in cytotoxic granules. acts as a scaffold, forming a complex with perforin and the granzymes