T-Cell Mediated Immunity Flashcards
Cell-mediated immunity=?
What does it respond to?
T cell immunity
Responds to intracellular microbes
What must we do to clear infection?
Must clear all microbial reservoirs (natural source of a microbe: which cells infected? Must get rid of), including our own infected cells
Which microbes require CMI control?
Intracellular microbes
How do we get from initial exposure to effector cells?
Dendritic cell comes in and activates CD8 (does NOT result in death of dendritic cell). FIRST interaction is about ACTIVATION, then rest of recognition is death to the cell w/ the antigen: can only replicate inside of cells
Cells activate, leave lymph, travel to site of infection, helpers tell others what to do, CD8s target and destroy infected cells
What do CD8s Vs CD4s talk to?
CD8s work am non phagocytic cells and kill infected ones
CD4s talk with phagocytic
Define clonal deletion
Recognizing self-reactive cells (negative selection) and telling them to die (clone refers to single cell
Explain T cell activation and what T cell activation results in
TCR complex engages MHC and peptide (key1)
Full activation requires co-stimulation (key2) (think double keys for nuclear launch)
Activation results in:
- stimulation of innate and adaptive responses
- cytokine production and release
- inflammation
- CTL activity
- b cell regulation
What are the characteristics of a naive T cell?
Mature, but never been activated, has survived maturation process
Overview of T cell activation
1) antigen and co stimulation –> IL-2R (cytokine) activation and differentiation
2) cell secretes IL-2 and creates more (+ feedback loop)
3) IL-2: made for T cells for T cells= forces them to divide
4) after divided: leaves and is now called effector cell (in peripheral tissues)
5) small proportion differentiate into memory cells (long lived, keep populations up)
IL-2R versus IL-2
IL-2R is a cytokine, for activation and differentiation
IL-2 is positive feedback loop that forces T cells to divide
Effector cells, memory cells
Effector: activated and now doing work
Memory: previously activated cells (both b and T cells make them)
What are the 3 signals that a T cell receives during activation
1: TCR complex with MHC and antigen interaction (key1) must recognize both MHC and antigen
2: co-stimulation signal between CD28 (t cell surface) and B7 (surface of APC) (key2)
3: cytokines released by APC, signal tells helper T cells what form of helper t to become (1,2,17)
List T cell activation ligand-receptor pairs
T cell: APC
CD4/8 : MHC class 2/1 (signal transduction)
TCR (a/B chains) : peptide/antigen&MHC
(Antigen recognition)
CD3 : no ligand
(Signal transduction)
Zeta chains : no ligand
(Signal transduction)
CD28 : B7
(Costimulation)
Adhesion : ICAM-1
What is costimulation and why is it important for T cell activation? What happens if costimulation doesn’t occur?
B7 (APC) with CD28 (t cell)
AND MHC with TCR
Both needed to activate T cell
If costimulation doesn’t happen–> no response or tolerance, cell is turned off
(APCs only make B7 when they have engaged right receptors: been activated by binding TLR, so no costim= prob no microbial antigen, presenting with costim only happens when APC recognizes foreign)
If it does: activates and secreted cytokines
Central tolerance?
Positive and negative selection during maturation
Another later of tolerance, presenting with costim only happens when dendritic cell recognizes something foreign
How are CTLs activated?
Cell is infected with microbe
Phagocytosis by host APC (dendritic present MHC 1&2, can activate both)
TCR recognized MHC and antigen AND costimulation
Activation
*note: CD4 activation can lead to secretion of cytokines that help activate CD8
For activation of T cells: always need TCR:MHC&antigen recognition AND costim
What happens after T cell activation?
T cells talk to macrophages and B cells via cytokines
B cells --> class switch and antibody secretion Macrophage activation: destruction of phagocytosed antigen
CD8s: seek out infected cells w/ same antigen as they were activated with once activated
Killing of infected cells
What is the function of IL-2?
IL-2 is secreted after T cell activation by antigen and costim
IL-2 receptors are also made
Sole purpose of IL-2 is for the CELL to DIVIDE
Positive feedback loop that drives more division
IL-2= proliferation
T cell expansion and decline
Clonal expansion, contraction, only memory cells left behind (non memory cells die)
Vaccines
Live-atenuated: robust response probs
Flu: shot is dead inactivated, intranasal is live attenuated and stays in upper respiratory tract, doesn’t make it to lungs
Intranasal: get serum and mucosal protection, better memory
Shot dead inactive is only serum protection
Helper T cell subtypes?
TH1: activates macrophages and B cells, standard pro-inflammatory response, works back&forth with innate
TH2: anti-inflammatory, antagonistic to TH1 (prevent each other) because cytokines inhibit each other’s pathway
TH17: similar to TH1, mediate neutrophil response, guide them to sit and for their action, pro-inflammatory
1&17 can work together (pro-inflammatory and activate innate cells
T1&T2 are mutually exclusive in the same region
What dictates what type of helper T cell it will become?
Cytokines
Cytokines secreted by APC and resulting TH cell. What they secrete, and pro-anti inflammatory
IL-12 and IFN-y –> TH1 –> secretes IFN-y–> macrophage activation, proinflammatory
IL-4 –> TH2 –> secretes IL-4 (leads t B cell class switch to IgE: mast cell de granulation and allergies) and IL-5 (eosinophils activation), anti inflammatory.
TGF-B & IL-6 –> TH17–> secretes IL-17–> proinflammatory and increased neutrophil response
What do T cell secreted cytokines tell B cells to do?
Class switch (antibodies). Tells them what to class switch to
Antibodies if B cells have effector functions. Not the B cells themselves!!
TH1 vs TH2 balance
Their cytokines negatively inhibit each other
Vs some pathogens this causes differing results:
Tuberculoid leprosy is isolated (granules surrounded by T cells: TH1 normal response) whereas lepromatous leprosy cannot be contained (defective TH1)
Recall TH1 leads to normal macrophage activation
CTLs at work (CD8 here): effector function
Perforin and granzyme function
CD8 only has one effector function: look for cells infected with same antigen that activated them and kill them
Perforin: creates pore
Granzyme: activate apoptosis, cell death cascade, tells target cell to self destruct
One cell at a time only
When is complement activation required
Only to activate the b and T cells
Once activated, CD8s no longer need complement, only MHC and antigen
NK cells activation and inhibition
If inhibitory receptor engaged –> not activated and no killing
If not engaged–> activated and kills infected cell
NK is not antigen specific
Takes care of the cells that cannot talk to CD8, such as when a virus turns off a cells ability to say it’s infected
T cell activation summary
APC: MHC&peptide, B7, adhesions (ICAM-1) hold them together long enough for rxn to take place
T cell: TCR w/ CD3&4/8, CD28, integrins (LFA-1) –> both MHC and antigen recognized =activation
CD4 tells other cells what to do, CD8 just kills infected
What are gamma-delta T cells?
Small (10%) subset of T cells that can bind w/o MHC restriction. Appear to have more of an innate function, recognize broad antigens
Found in intestinal and pulmonary epi
Epi surveillance for UV damage, infection, and cancer
How do T cells tell other cells what to do?
CD40 ligand (on T cell) binds to CD40 (on target cell) binding activates the target cell
Macrophages: are activated and start killing phagocytosed microbes (cell-mediated), cytokines as well
B cells: activate via CD40, T cell cytokines tell them which Ig to make
T cell is SENDING the signal now!
Cell mediated immunity overview
CD4 TH1&17 recognize antigen on APC, cytokine secretion, macrophage activation and inflammation
CD8recognizes activates and tells cell to die
What do you need cell mediated response for?
Intracellular pathogens
Such as Listeria, an intracellular bacteria
Does serum transfer specific immunity?
No, need a cell mediated response to deal with intracellular pathogens
Serum=do not fight off listeria
Serum= antibodies/humoral response
What type of cell must be used to fight intracellular pathogens?
T cell response is needed, so that they can activate macrophages which do the killing
CD4s activate macrophages
CD4 doesn’t kill listeria itself, but it activates the cells that can
When a T cell TH1 for example, activates its target cells it…
Gets them to work harder
What are responsible for pulling naive T cells to get into lymph?
CCR7, L-selection, and sphingosine-1P
S-1P is high in blood and lymph, low in nodes, this gradient pulls it in, then pulls it back out
These are turned off once the cells become effector cells
HEV has ligand for L-selectin
Chemokines that bind CCR7 only made in lymph tissues
Once activated, how do T cell receptor expressions change?
Once they enter through the HEV, and become activated, they turn off CCR7 and L-selectin and turn in receptors that correspond to tissue
Remember: T cells exert effector functions at the site of infection, so once activated they want to leave lymph
How do T cells get out of lymph tissue?
S1P is high in blood/lymph and low in nodes
Binding to its receptor reduces expression of receptor
If not activated: receptor expression increases and it leaves through efferent lymph vessel
If activated: receptor expression is repressed
Eventually expression is restored and l-selection and CCR7 are turned off, drawing cell out of lymph
Effector T cell migration summary
Effector cells migrate to site of infection
They do NOT express L-selectin or CCR7 (naive off)
Endothelium expresses: E&P-selectins and ICAM1&VCAM1
Activated T cell expresses: propor E&p-selectin ligands and integrins LFA-1&VLA-1
E&P selectin and ICAM1&VCAM1= effector ON
L-selectin and CCR7= naive OFF
How cells stop at tissue
Rolling adhesion: selections Integrins activation by chemokines--> to high affinity state Stable adhesion (high affinity integrins) Migrate through Endo cells to infection site
How do Cd4/8 work together?
CD4 tells macrophages to work harder, if macrophage can’t kill an infected cell it ingested, then CD8 kills it
Resistance to CMI
Herpes and mycobacterium
Herpes shits down process of cell destruction, such as shutting down MHC class 1 presentation
Mycobacteria: inhibit phagolysosome fusion
True pathogens find a way to avoid immune response: escape recognition, colonize, before immune system recognizes
Clonal selection
Only activate antigen-specific T cells, so only clones that recognize specific antigens
