T Cells

Question 1

Types of T cells

Answer 1

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 *

Question 2

Gamma-delta T cells

Answer 2

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

Question 3

Stages of T cell maturation

Answer 3

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

Question 4

Goldilocks principle

Answer 4

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”

Question 5

Accessory molecules of T cells that play roles in signal transduction

Answer 5

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

Question 6

Accessory molecules with T cells that play a role in stabilizing/adhesion

Answer 6

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

Question 7

Accessory molecules with T cells that play a role in constimulation

Answer 7

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

Question 8

Accessory molecules with T cells that play a role in the inhibition cascade

Answer 8

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

Question 9

CTLA-4 in the role of cancer

Answer 9

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

Question 10

T cell activation

Answer 10

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

Question 11

T cell transcription factors

Answer 11

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)

Question 12

CAR T

Answer 12

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

Question 13

Cyclosporin and Tacrolimus

Answer 13

Drugs that Inhibit T-cell activation via preventing IL-2 release due to inhibiting NFAT generation

Used in RA, autoimmune issues and organ transplants

Question 14

Difference between effector and memory T cells

Answer 14

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

Question 15

Types of effector helper T-cells

Answer 15

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

Question 16

Cytokines environments and what type of effector T-cell do they initiate

Answer 16

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

Question 17

Specific differentiation of TH1 cells

Answer 17

• 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

Question 18

Specific differentiation of TH2 cells

Answer 18

• 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

Question 19

Specific differentiation of TH17 cells

Answer 19

• 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*

Question 20

TH1 primary job

Answer 20

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

Question 21

TH2 primary job

Answer 21

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

Question 22

TH17 primary job

Answer 22

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

Question 23

Cytotoxic T cells (CTLs)

Answer 23

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

Question 24

Perforin and granzymes

Answer 24

Perforin: Pore forming protein that pokes holes in target cells to allow granzymes in

Granzymes: trigger apoptosis cascade via caspase C

Question 25

FAS-FasL

Answer 25

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*

Question 26

TNF/LT role in apoptosis

Answer 26

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

Question 27

Superantigens

Answer 27

*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

Question 28

Cell mediated immune response broad function

Answer 28

To kill intracellular pathogens and tumor cells Include T cells macrophages and NK cells

Question 29

IL-12 part in intracellular bacteria infections

Answer 29

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

Question 30

CD40: CD40L

Answer 30

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

Question 31

What happens if a macrophage cannot kill infection even after stimulation of IFN-y

Answer 31

Cytotoxic T-cells finish the job by the macrophages up regulating MHC 1 with the pathogenic antigen present - kills macrophage

Question 32

First line of defense against viruses

Answer 32

Type 1 interferons (IFN a/b) release is stimulated and the activity of NK cells are turned on

Question 33

IFN a/b actions

Answer 33

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

Question 34

The antiviral state overview

Answer 34

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.

Question 35

What cytokines activate NK cells and how specifically?

Answer 35

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

Question 36

Memory T-cell board overview

Answer 36

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

Question 37

Two subsets of memory T cells

Answer 37

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

Question 38

T cell exhaustion

Answer 38

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*

Question 39

Regulatory T-cells

Answer 39

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*

Question 40

What are the specific actions of regulatory Tcells

Answer 40

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

Question 41

Intracellular Bacteria and the immunological synapse

Answer 41

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