1. T-Cell Mediated Immunity Flashcards
Each T cell recognizes only 1 specific non-self peptide. How is this possible?
There is a large TCR repertoire, so they can recognize any Ag, this occurs in the thymus
What dictates the different immune responses by the two phenotypes of T helper cells, Th1 and Th2?
The different cyotkines they produce
Where do CD4 and CD8 attach to on MHC class II and MCH class I respectively?
To the non-polymorhpic/non-variant part (not the part involved in peptide binding
What are CD4 and CD8 called and why?
Called co-receptors because they are involved in signaling/activation
Naive T lymphocytes recirculate through the LN, and are activated there when they encounter TCR specific Ags. How are the Ags transported from the periphery to the LNs?
By mature dendritic cells (activated)
Naive T cells transiently interact with many DCs with antigens until it finds the specific one for their TCR. Upon antigen recognition naive T cells are activated to differentiate into effector cells and then can do what (2)?
remain in the lymphoid organs to help B lymphocytes
migrate to sites of infection to help activate macrophages
Ag recognition induces IL2 secretion by naive T cell, which allows clonal expansion, resulting in proliferation and differentiation of the T cells into…?
Effector or memory cells
The effector CD4 T cells respond to Ags by making cytokines which recruit and activate leukocytes and activate B cells. The CD8 CTL effectors will do what?
Kill infected and altered host cells
What are memory T cells
Long lived cells with an enhanced ability to react against the Ags
There are three signals that are required for T cells to proliferate and differentiate into effector and memory cells. These are?
- Ag recognition (signal 1)
- Costimulation (signal 2)
- Cytokines (signal 3)
Naive T cells can recognize antigens by DCs only, while effector T cells can recognize them by what?
Tissue Mø and B cells
What composes the signaling complex CD3?
Gamma Epsilon, Epsilon Sigma, and Zeta Zeta
Immunoreceptor tyrosine-based activation motifs (ITAMs) are the regions of signaling proteins that are phosphorylated on tyrosine residues and become docking sites for what?
Tyorsine kinases
Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) are the regions of signaling proteins that are sites for WHAT, that counteract actions of ITAMs?
Tyorsine phosphatases
Superantigens (SAgs) produce by bacteria are the most powerful T cell mitogens ever discovered, needing less than 0.1pg/ml of a SAg to stimulate T cells in an UNCONTROLLED manner, resulting in?
Fever, shock and death due to toxic shock syndrome
SAgs bind MHCII molecules on the outside of the binding groove on the V region of the B subunit of the TCR. Once bound, they release massive amounts of proinflammatory cytokines such as..?
TNF, IL1, IL2
An example is staphylococcal enterotoxins (SE), a SAg that causes food poisoning and toxic shock syndrome toxin (TSST)
Once the first signal of T cell stimulation is accomplished by antigen recognition, the APC is activated and increases expression of costimulators, which secrete cyotkines (IL2). What are the main costimulators for T cell activation?
CD28(T)/B7-1 or B7-2(APC) for stimulation
CTLA-4(T) /CD80/CD86 (APC) (same as B7) for inhibition
What is the main activator of APCs so they are able to use costimulators to activate naive T cells?
Microbes and cytokines activated during innate immune responses (inflammation)
What is a cytokine released by activated DCs which stimulate differentiation of naive T cells into a Th1 type / effector T helper cells?
IL-12 (the third signal)
CD28 is expressed on T cells and binds B7-1(CD80) and B7-2(CD86) on activated APCs. How do the CD28 signals work with Ag recognition?
In cooperation to promote survival, proliferation, and differentiation of Ag-specific T cells
DCs, Mø, and B cells express B7-1 and B7-2 (CD80/86) which can bind to CD28 and stimulate Naive T cells& generate regulatory T cells. Or it can bind to an inducible T cell receptor, CTLA-4 which does what? (have Tyr-X-X-Met on tail inside cytoplasm for signaling)
Negative regulation of the immune response &self tolerance
DCs, Mø, and B cells express the ligands ICOS-L (CD275) (inducible T cell COStimulator ligand), which binds to ICOS on T cells and does what? (have tyr-x-x-met on tail inside cytoplasm)
Costimulation of effector and regulatory cells, generation of follicular helper T cells
Mø, B cells; endothelial, epithelial and tumor cells (PD-L1 only) express PD-L1 (B7-H1,CD274) and PD-L2 (B7-H2, CD273), and stimulates PD-1 on T cells, B cells and myeloid cells and does what? (has ITIM/ITSM motif on tail)
It signals for negative regulation of T cells
PD= program death
CTLA-4 is stored in intracellular vesicles and is not expressed in naive and memory T cells. Once the TCR is triggered by Ag encounter the CTLA4 is transported to the cell surface. What is the main function of CTLA4?
A signal dampener to strong stimulation of CD28, to maintain a consistent level of T cell activation (not too strong or weak)
The major role of programmed cell death protein 1 (PD1) is to regulate inflammatory responses in tissues by effector T cells recognizing Ags in the peripheral tissue. Activated T cells upregulate PD1 and inflammatory signals in the tissues induce the expression of what?
PD1-ligands, which downregulate activity of T cells and limit collateral tissue damage in response to infection of the tissue
PDL1 induction is best produced by IFN-gamma from Th1 cells. if there is an execessive amount of PD1 on T cells where there is chronic Ag exposure, it can induce what?
an exhausted or anergic ( :( ) state in T cells
Once T cell is activated, cytokines in the T cell environment determine outcome of Ag recognition in regards to the effector T cell differentiation… IL12 activates signaling molecule STAT 4, which expresses T-bet and generates?
Th1 cells
IL4 activates STAT6 which expresses GATA-3, which generates?
Th2 cells
IL6 activates STAT3 which expresses reinoic acid receiptor-related orphan receptor-gammat (RORGt), which generates?
Th17 cells (memory T cells)
TGFB activates signaling molecule SMAD2-SMAD4 and promotes expression of FOXp3 which generates?
T regulatory cells
CTLs are activated in the LN and proliferate there. They contain numerous granules called lysosomed that contain perforin and granzymes used to kill other cells. What cyotkine do CTLs release to activate macrophages?
IFN-gamma
IFN-G, perforin and granzymes are regulated by what?
transcriptional factor T-bet
Once the Ag has bound to TCR, LCK is activated on CD4/CD8 and brings CD8/4 close to CD3 and phosphorylates ITAMs on what?
the Zeta chains of the CD3 signaling complex
When both ITAMs are phosphorylated, they bind ZAP-70 via SH2 domains. Then ZAP-70 is phosphorylated by LCK resulting in?
activation of ZAP-70 catalytic activity
Once ZAP-70 is activated, it phosphorylates LAT and SLP-76 which functions as what to recruit other signaling molecules?
scaffolds!
Once LAT is phosphorylated, it recruits GADS and GRB2, GRB2 phosphorylates and activates PLC1 (phospholipase C1), which produces what?
PLC1 produces inositol 3-4-5 triphosphate (IP3) and diacyglycerol (DAG)
IP3 increases cytosolic Ca2+ and NFAT activation and DAG activates PKC (protein kinase C) which activates NF-kB. DAG will also activate Ras which activates?
MAPK pathways and AP-1
There are many changes in CD4 T cell protein expression after activation before the T cells start to divide and proliferate. List the main thing expressed during each stage.
Rentention in LN
Proliferation
Effector Functions
Control of response (after proliferation)
- CD69
- IL-2RA
- CD40L
- CTLA-4
What is the highest level transcription factor within the first few hours after the APC brings the antigen to the TCR and activates it?
c-Fos transcription factor
IL2 has many biologic actions… IL2 is an autocrine GF for CD4/8 T cells, gives cyotoxicity of NK and CD8 cells, Costimulates T cells to produce IL4,5and IFN-g, promotes the development of T regulatory cells and induces what?
autocrine actication-induced death in T cells
There are many function properties of IL2 such as…
It stimulates the survival, proliferation and differentiation of Ag-activated T cells:
IL2 induces anti-apoptotic protein Bcl-2
Stimulates cell cycle progression by degradation of inhibitor P27
Helps with survival/function of T reg cells:
IL2 or IL2R -/- KO mice have defects in T reg
IL2 has been shown to stimulate proliferation and differentiation of _______ and ________ in vitro
NK cells and B cells
Once a T cell is activated, CD69 expression changes. CD69 binds to CD69L and reduce expression of sphingosine-1-phosphate receptor (S1PR1). As a result, activated T cells are retained in LN to receive signals that initiate proliferation and differentiation into?
Effector and memory cells
Expression of S1PR1 on both CD4/8 T cells and S1P gradients between lymphoid organs and circulatory fluids play a key role in?
T cell egressing from the LNs
After cell division, CD69 expression decreases and the activated T cells re-express high levels of S1PR1 allowing what to occur?
Effector and memory cells to exit the lymphoid organs
When a T cell is activated by Ag and costimulation, IL-2RBY complex will change conformation into high-affinity IL-2RABG (CD25) complex, which will bind all the released IL2 and cause what?
T cell proliferation!
The last highly expressed marker during T cell activation is CD40L. Ag recognition induces expression of CD40 on the DC. Then CD40L (CD154) increases in the activated T cell about ________ hours after Ag recognition?
24-48 hours
The expression of CD40L enables T cells to help APCs to become better APCs. This is done SOMETIMES by stimulating the expression of more B7 molecules and what?
The secretion of cytokines that activate T cells
Elminating the Ag leads to contraction of T cell response. This is responsible for maintaing ________ in the immune system.
Homeostasis
As costimulation and IL-2 levels drop, the levels of anti-apoptotic proteins drop. IL2 starvation leads to mT intrinsic pathway of apoptosis. Along with this, contraction of T cells is also contributed to? (3)
- inhibitory receptors CTLA4, PD-1
- Apoptosis by death receptors TNFRI and Fas
- Inhibition by T reg cell products
What has the most abudandt lymphocyte population in the body during your lifetime, stored in tissue, lymphoid tissues, intestines, lungs and skin?
Memory T Cells
The type of transcription factor released during T cell activation can influence whether the cell becomes memory or effector…Which TFs?
CD4 T cells = driven by T-bet
Memory cells= promoted by Blimp-1
DNA methylation determines function and status among naive effector and memory cells. Effector and memory have LESS methylation than naive and same chromatin accessibility pattern. What does this confirm?
Memory T cells are generated from effector T cells through epigenetic modifications
Memory T cells respond in 1-3 days while naive take 5-7, the number of memory cells that are specific for ant Ag is greater than naive cells for the same Ag, and WHAT do memory cells have increase levels of and why?
They express increased levels of anti-apoptotic proteins which may be responsible for prolonged survival
Memory cells are able to migrate to peripheral tissues by adhesion molecules and chemokine receptors to respond to an Ag. The are slow self-renewing (long life span) and maintanence depends on which cytokines that do what?
Cytokines IL7 and IL15 which induce expression of anti-apoptotic proteins and stimulate low-level proliferation
There are three stages of memory T cells. 1) memory generation which occurs usually ages 0-20. 2) memory homeostasis which is where they plateau and maintained by homeostasis, ages 30-65. 3) ?
Immunosenescence which is during ages 65 and greater and means the gradual deterioration of the immun system
Central memory T cells (Tcm cells(CD8)) ‘home’ mainly in LNs, spleen and blood. Which proliferate (high IL2) and generate many _______ when Ags are present.
effector cells
Effector memory T cells (Tem cells(CD4)) circulate in the blood and DO NOT proliferate but produce ____________ or become cytotoxic
IFN-gamma and TNF (for macrophages)
Resident tissue memory T cells (Trm cells) reside in epithelial barrier tissues between host and environment. They produce IFN-g and TNF and are specific for?
Pathogens and Ags that have been encountered previously through that epithelium barrier where it resides
Naive T cells home to LNs as a result of _______, ______, and _______, which bind to the LNs ligands expressed on high endothelial venules (HEVs)
L-selectin, LFA-1 integrin, and chemokine receptor CCR7
For the T cells to leave the LN, ________ binds to the receptor _______
the phospholipid sphingosine 1-phosphate (S1P) binds to S1PR1 (type 1 sphingosine 1-phosphate receptor)
Naive T cell L-selectin binds edonthelial L-selectin ligand and has intial weak adhesion of T cell to HEV. LFA 1(B2integrin) binds ICAM-1 on endothelial allowing stable arrest on HEV CCR7 (Naive t cell) binds CCL19/21 and does what?
Activates integrins and chemotaxis
Activated (memory/effector) T cell
E and P selectin ligand binds E/P selectin leads to weak adhesion of T cell at peripheral site infection
LFA-1 or VLA-4 (B2integrin/B1integrin) bind ICAM1 or VCAM 1 for stable arrest on cytokine activated endothelium
CXCR3 bind CXCL10 and does what?
activates integrins and chemotaxis
