Cytotoxic T and Natural Killer Cells Flashcards
What is the first step in the activation of the adaptive immune system, and how are cytotoxic T cells activated?
-Activation of T helper cells by Antigen presenting MHC-II DC
-PAMP-PRR-induced cytokines secreted by APC to stimulate T helper differentiation to direct the immune response
-T helper cells proliferate and secrete cytokines to stimulate antigen-specific Tc and B cells
What are the two ways how an APC activates a cytotoxic T-cell?
- Sequential: APC presents MHC-II antigens to T helper cells -> license to present it through MHC-I to naive T-cells -> Naive cell develops to a CTL
- Simultaneous: Antigen presentation through MHC-I and MHC-II to T helper and naive T cell at the same time
-> this way is more effective
-CTL dont require signal 2 (CD28 - CD80) or signal 3 (cytokines) anymore
What are the two pathways used by cytotoxic effector T cells to kill their target cells and how are cytotoxic effector T cells different from neutrophils in terms of cell killing?
-Perforin/granzyme pathway and Fas/FasL pathway
-One difference is that Neutrophils secrete their granules by spreading them, and also causing damage to adjacent tissues, effector T cells get close to their target and release granules right upon the target cell
What is the Perforin/granzyme pathway?
-Perforin monomers are exocytosed on the target cell to build Pores in the membrane -> now granzyme B (protease) can get in and activates caspases-3 by cleaving it -> APOPTOSIS
IN CLASS QUIZ: Which PRR is involved in caspase-mediated pyroptosis with the help of inflammasomes?
NLRs -> activates inflammosomes -> activate caspase -> APOPTOSIS
-happens when a cell decides to undergo apoptosis bc infected
Explain the Fas-FasL pathway?
-cytotoxic effector cells create vesicles with FasLigand
-Vesicle fuse with cytotoxic effector membrane and shift FasL to the cell surface
-Cell-Cell interaction to Fas receptor on the target cell (all cells should have that unless downregulated by a pathogen)
-Caspase cascade: Caspase 8 -> Caspase 3 -> death signal -> APOPTOSIS
What are some T cell effector subset types?
Tc1 for intracellular pathogens: (similar to TH1) secrete IFN-γ but no IL-4
-> use perforin and Fas pathway to kill
Tc2 for extracellular worms: (similar to TH2) secrete IL-4 and IL-5, much less IFN-γ
-> use perforin to kill
If they use perforin and Fas why are they secreting IFN g and ILs for?? -> answered: for communication with other cells, maybe telling them which path to differentiate
-> maybe similar to T helper to activate macrophage killing (IFN-g) and B cell antibody production and Neutrophile activation (IL-4,5)
What is the difference between a NK cell and a cytotoxic T c ell (CTL)
-NK cells are part of the innate immune system, they look like CTLs but they dont have TCR
-CTLs have fully recombined TCRs
-NKT cells are inbetween they look like NK cells but they have TCR (but not as variavle as CTLs)
What is the function of NKT cells?
-They recognize glycolipids presented by CD1
-can act as a helper or killer cells (Fas-FasL)
-No memory cells
-have NK surface proteins, rather than T-cell varieties
How do NK cells work?
-No TCR, no receptor gene arrangement
-NK cells help regulate innate/adaptive immunity with cytokines
-they recognize and destroy infected and cancer cells
How do NK cells recognize their targets, since they don’t have TCRs??? -> with activating receptors (no MHC as a signal to KILL) inhibitor receptors
How does the NK cell response look like?
-They are innate, so they always circulate
-They can be upregulated with IFN-γ
-They recognize the balance of activating and inhibiting NK receptors, which tell to kill or not to kill a cell
-Lack of MHC-I is a major signal to kill -> bc viruses f.e. like to prevent MHC-I presentation to not expose themselves
-Once activating cell signal overweigh they kill by perforins/granzymes
What is the purpose of the activating and inhibitng signal balance?
Every cell has activating signal (KILL) and inhibiting signal (NOT KILL) one reason is bc they undergo stress or something is going wrong (cancer, cellular damage) and in case they need to get killed they switch the balance and upregulate the activating signal
How do NK cells “receive” their license to kill?
-By prior interaction with a healthy cell through MHC-I (inhibitory signal) and not killing it -> to see if it has the ability to not kill healthy cells
Why do NK cells upregulate faster than CTLs
-Because CTLs have TCR specific for pathogens, the number of CTLs with specific TCR are fewer that’s why it takes time to build up the number; but NK cells don’t have TCR so there are more NK cells ready to be upregulated
ORDER:
How do cells fight mutations and why do they still turn into tumors?
-Cells undergo checkpoints throughout their cell replication cycle, whereby they are screened for mutations and repaired
-Mutations on checkpoint proteins disorders the checkpoint process, leading to the accumulation of mutations
What is the difference between benign and malignant tumors?
-Benign: unable to invade surrounding tissues, and no indefinite grwoth
-Malignant: becomes more invasive, may metastasize and invade other distant tissues
How does the immune system detect tumor cells, since they are self and immune cells should not recognize them? (bc of central tolerance (bone marrow and thymus) and peripheral tolerance)
4 groups of antigens recognized by T cells:
-Ag expressed only by tumors (f.e. viral proteins HPV)
-Ag of the mutated form of a normal gene
-Ag expressed at a certain stage of development
-Ag overexpressed in certain tumor
IN CLASS QUIZ 1
If cancer is an intracellular disease, which T-helper response would be the best for it?
TH1
What are tumor-specific antigens (TSA) and why are they not detected easily by t cells, since they are not self anymore?
-They are unique sequences leading to altered proteins (nonself),
-bc developing T cells are presented with thymus self cells (negative selection) and TSA are non-thymus cells
-TSA: best case bc now they are specific (f.e. prostate-specific antigen) and look like a different protein shown at MHC-I to activate T -cells by the cross-presenting process
How are they recognized since the self has no CD80 -> T effector doesn’t need signal 2 -> and now they recognize altered self-antigen as foreign -> KILL
What are tumor-associated antigens?
TAAs are normal cellular proteins with unique expression patterns (escape peripheral tolerance bc they are not exposed a lot to T cells with CD28 - CD80 check)
->not exposed because: fetal cell and only expressed in fetal stage or antigens expressed at very low level or their expression is dysregulated
How does the body deal with mutated cells?
- intrinsic suppression: repair of DNA mutations or APOPTOSIS through inflammasomes
- cytotoxic cells:
-NK cells sense increased expression of activating ligands (signal to KILL) due to stress caused by f.e. unfolded proteins due to mutations
-IFN-γ and IL-12 encourage DC to activate strong TH1 and CTL response
(remember: IL-12 -> TH1 -> IFN-γ -> macrophage killing)
-T helper and cytotoxic can detect tumor antigens
How do cancerous cells escape the host immune response?
-After multiple mutations, they get less responsive to immune clearance
-Downregulation of tumor antigens or NK activating ligands (stress) -> poor target for NK cells
-Shutting down the Fas-FasL pathway (don’t express Fas anymore) -> poor target for CTLs
-reduced MHC expression -> poor target for CTLs and NK cells
Further strategies of cancer cells to escape immunity:
-Loss of adhesins -> cells use adhesins to stick to each other -> without adhesins tumor cells can migrate to blood vessels and metastasize
-Expression of anti-inflammatory markers (IL-10 and TGF-ß) to show that there is no infection going on -> sensed by Treg
