T Cells Flashcards
Types of T cells
Cytotoxic T cells (CD8): induces dell death with direct cell contact via MHC 1
Helper T cells (CD4): produces cytokines and antibodies to modulate the adaptive immune system
Regulatory T cells: suppress the adaptive immune response
- all T-cell receptors ONLY respond to cell-associated antigens w/ MHC, not free floating antigens *
Gamma-delta T cells
Is the only exception to the rules of TCR binding
- recognize either free/processed antigens (lipids or peptides)
- affects are unknown but hypothesized to play a part of autoimmunity
Stages of T cell maturation
1) Pro-T cell
- proliferation and initiation of somatic recombination of the B-Chain
2) Pre-T cell
- initiation of somatic recombination of A-chain
3) immature T cell
- expression of TCR
- Expression of both CD4 and CD8 (double positive stage)
4) Mature T cell
- down regulates one of CD4 or CD8 which then solidifies the T cell as a cytotoxic or helper
Goldilocks principle
Explains positive and negative selection for T cells maturing in thymus
- positive = weak recognize MHC self-peptides (survival)
- negative = too strong or no recognition of self-peptides within MHC (apoptosis)
“Not too strong and not too weak, just right”
Accessory molecules of T cells that play roles in signal transduction
CD3, Z-chain, and ITAMs
- produce a signal to the cell itself via interactions with Lck protein saying that the cell is bound to a proper receptor and needs to start acting
Accessory molecules with T cells that play a role in stabilizing/adhesion
CD4 or CD8 receptors and LFA-1: ICAM-1
- reach out and bind to the MHC 1/2 molecules and once bound, release Lck protein which in turn interacts with the signaling molecules
Accessory molecules with T cells that play a role in constimulation
CD28 -> B7
CD28 binds to B7 and enhances stimulation of the cells action
Co-stimulates with CD3 and ITAM which are turned on via CD 4/8: MHC 2/1
Accessory molecules with T cells that play a role in the inhibition cascade
CTLA-4 and PD-1 -> B7
Once the pathogen is killed or released, the CTLA-4 and PD-1 signals will block CD-28 binding to B7-1 down regulating actions of the cells
CTLA-4 in the role of cancer
Using antibodies to attack CTLA-4 receptors forces cells to not “tolerate” cancer and instead kill it
-also kills some self cells but its give and take
initially tolerate cancer because cancer processes self antigens
T cell activation
Usually occurs in 2nd lymphoid tissues and requires two activation signals
* if one or the other signal is not present, the T cell will NOT activate*
- always requires naive T cell interactions with APC’s
- signals are usually CD4: MHC2 or CD8: MHC1
And B7 : CD28
Once turned on, the T cell releases IL-2 which autocrines the T-cells and tells them to proliferate via JAK/STAT pathway
T cell transcription factors
Produced after the T-cell is turned on and produces CD3 cell activation signal.
- NFAT
- NF-kB
- AP-1
All function to initiate transcription of the IL-2 gene for T-cells (required for T-cells to proliferate and become an army)
CAR T
Inserting the gene into a T-cell forces the T-cell to be specific towards a certain peptide (usually cancer).
- next requires IL-2 cytokines to initiate T-cell proliferation and then you have an army of T-cells specific only for one peptide
Cyclosporin and Tacrolimus
Drugs that Inhibit T-cell activation via preventing IL-2 release due to inhibiting NFAT generation
Used in RA, autoimmune issues and organ transplants
Difference between effector and memory T cells
Effector T-cells: short lived cells responsible for primary/innate immune responses
- hyper and cytotoxic
Memory T-cells: long lived cells that response to subsequent infections with heightened sensitivity
Differentiation is hypothesized to occur within 1-2 days after activation
Types of effector helper T-cells
TH1: primarily involved in controlling cell-mediated reactions
- react to bacteria, viruses, fungi (INTRACELLULAR)
TH2: primarily involved in controlling humoral reactions
- react to parasites and allergens (EXTRACELLULAR)
TH17: primarily involved in inflammatory disorders and microbial defense
- extracellular pathogens and role in auto immune disorders
T regulatory: contractions and inhibition of the immune response
Cytokines environments and what type of effector T-cell do they initiate
IL-12 (1st) and IFN-y (2nd) = TH1
IL-4 = TH2
IL-6 and TGF-B =. TH17
Arise from DCs and, NK cells and macrophages
Specific differentiation of TH1 cells
- Intracellular microbes invade APC cells
- Dendritic cells recognize infected cells and releases IL-12 primary release
- NK cells recognize infected cells and release IFN-y secondary release, occurs when MHC is down regulated in infected cells
- both IL-12 and IFN-y stimulates JAK to phosphorylate STAT to transcribe STAT 1/4 and T-bet to induce the TH1 T-cell
Specific differentiation of TH2 cells
- parasites invade the body/cells
- mast cells, eosinophils release IL-4 during interact with the parasites
- also occurs via autocrine function from other TH2 in the absence of IL-12, this is not fully understood though*
- IL-4 initiates JAK to phosphorylate STAT to transcribe STAT6 and GATA-3 which helps promote TH2 maturation
Specific differentiation of TH17 cells
- extracellular fungi, bacteria invade
- dendritic cells recognize this and secrete TGF-B and IL-1/6/23
- also found in the mucosal surfaces of the body naturally as a evolutionary mechanisms
- initiates JAK to phosphorylate STAT to produce STAT3 and RORyt proteins which help mature TH17 cells
- TH17 cells also secrete IL-21 so this also functions in an autocrine function in the presence of extreme inflammatory conditions*
TH1 primary job
Activating supporting phagocytes against intracellular infections, and to recruit more immune cells
Secrete 3 cytokines in order to increase macrophage activation, and recruit more immune cells
- IFN-y
- IL-2
- TNF-a
cytokines released form TH1 cells also activate and differentiate Cytotoxic T-cells
TH2 primary job
Stimulate B cells to produce antibodies and in eosinophil/mast cell immune reaction in response to extraceullar antigens
- also inhibit M1 macrophages and Cell mediated immunity, but promote M2 macrophages
Secrete 3 cytokines to do these functions
- IL-4
- IL-5
- IL-13
TH17 primary job
Increase synthesis of acute phase proteins, maintain autoimmunity and promote chemotaxis and extraversion of immune cells to the spot they need to be. Respond to extracellular pathogens
Secrete 3 different cytokines to do their job
- IL-17
- IL-21
- IL-22
also indirectly promote IL-6 release to increase inflammation
Cytotoxic T cells (CTLs)
Go around killing foreign pathogens that is programmed to kill based on MHC 1 : CD8 and CD 28: B7 interactions
3 mechanisms to kill
- Granzymes/Perforin
- FAS/FasL
- Cytotoxic Cytokines- TNF/ LT
must have cell-to-cell contact
Perforin and granzymes
Perforin: Pore forming protein that pokes holes in target cells to allow granzymes in
Granzymes: trigger apoptosis cascade via caspase C
FAS-FasL
FasL: binds to FAS receptors and initiates caspase C cascade (apoptosis)
- only activates when MHC: CD8 and CD28: B7 connections occur
- ALL nucleated cells express FAS receptors
- ONLY activated CD8 T-cells express FasL
- requires MHC: CD8 binding first to allow time for FASL to bind to FAS*
TNF/LT role in apoptosis
TNF: tumor necrosis factor
LT: lymphotoxin
Both are secreted via CT8 once MHC 1: CD 8 binding occurs. Induces apoptosis cascade by binding to the TNFR1 receptor that is up-regulated on cells marked for death
Superantigens
Staph and Group A strep are the most common ones
Superantigens bind the MHC: CD receptors together and wont let go, initiating cytokine storm (CD4) or mass unregulated expansion of T cells (CD8)
- results in fever, shock, organ failure and death if left untreated
Cell mediated immune response broad function
To kill intracellular pathogens and tumor cells
Include T cells macrophages and NK cells
IL-12 part in intracellular bacteria infections
1) secreted by macrophages in response to an infection that the macrophage cant kill its host
- binds to NK cells which secretes IFN-y to hyper activate both NK cells and Macrophages
Also stimulates TH1 cells by upregulating CD40L expression
CD40: CD40L
Binding of CD4 TH1 cells to macrophages that are having problems killing its infection
- stimulates IFN-y release from CD4 TH1 cells when bound and causes hyper action in macrophages
What happens if a macrophage cannot kill infection even after stimulation of IFN-y
Cytotoxic T-cells finish the job by the macrophages up regulating MHC 1 with the pathogenic antigen present
- kills macrophage
First line of defense against viruses
Type 1 interferons (IFN a/b) release is stimulated and the activity of NK cells are turned on
IFN a/b actions
Activates antiviral mechanisms in neighboring cells
Increase class 1 MHC expression, making it more likely to be attacked by CD8 T-cells
Stimulate NK cell activity in response to turning down MHC 1
*secrete via any cell when Toll-Iike receptors are bound to viruses in the intracellular cytosol
The antiviral state overview
1) type 1 IFNs land and activate neighboring cells via auto/paracrine fashion
- also activate NK cells to start searching for down regulated MHC
2) activates RNAse inside cell to chop up viral RNA before mass translation
3) viral replication is halted, reducing viral protein production until the CMI response can kill the cell.
What cytokines activate NK cells and how specifically?
Type 1 IFNs: increase overall activity
IL-12: stimulates secretion of IFN-y and TFN from NK cells
IL-15: stimulates NK cell proliferation and activation
Memory T-cell board overview
After innate and adaptive immune response to a certain pathogen, memory cells are formed in order to quickly combat future infections of the same pathogen
- secondary immune response
- two subsets of memory cells
- require IL-7 to maintain memory cell live (prevent apoptosis) and prevent over proliferation*
- only memory cells expressing IL-7R can live this long
Two subsets of memory T cells
Central memory T cells (TCM)
- live in secondary lymphoid tissue - proliferate quickly on secondary exposure and do most of the killing
Effector memory T cells (TEM)
- live in peripheral tissues (usually mucosal surfaces)
- secrete cytokines upon secondary exposure to get innate response quicker
T cell exhaustion
Can occur during chronic infections (usually viruses) that are very challenging to kill
- T-cells over time become exhausted and stop secretion of cytokines causing reactivation of a viral state
- most common pathogen is TB*
Regulatory T-cells
Suppressive CD4 T cells that down regulate immune response to minimize damage to self
- use the FoxP3 receptor unique to them and CTLA-4 to inhibit T cell responses
also inhibit auto-reactive T-cells
What are the specific actions of regulatory Tcells
Once the FoxP3 receptor is activated
- Express CTLA-4 receptors that inhibit T cells directly
- secrete anti-inflammatory cytokines IL-10 and TGF- B to turn down cytokine production As well as massively upregulated IL-2 receptors
- “hog” all the IL-2 cytokines to decrease proliferation of T cells
Intracellular Bacteria and the immunological synapse
When the stimulatory signals are binding to each other at the IS, some intracellular bacteria will use this as a “bridge” to cross to the T-cell and infect it
