Cell mediated immunity

Question 1

Clonal expansion

Answer 1

rapid increase in the number of antigen-specific lymphocytes. Any stimulation leads to proliferation,”You need many soldiers to win a war.”

Question 2

describe the activation of CD4 and CD8 cells. what is the juntion they create?

Answer 2

professional APC presents signals

1. signal 1= activation
   
   1. interaction between the TCR complx/CD4 or CD8 and the cognate peptide presented in the context of MHC2(CD4+ T cells) or MHC1(CD8 Tcells) on the APC
2. signal 2= survival
   
   1. interaction between co-stimulatory molecules CD28 on the T cell interacts with B7.1(CD80) or B7.2*CD86) on the APC
   2. creaates an immuniological synapse, lasting for hours -days
3. signal 3= differentiation
   
   1. cytokine-produced by APCs or other immune cells
   2. compostition of cytokine panel that delivers signal 3 influences the subsequent rffector funciton of the activated, prliferating DC4+
   3. signal 3 cytokines also induce CD8 to differentiate into CTL

Question 3

What is a CAM? what the 4 classes and six types of CAMs

Answer 3

1. Cell adhesion molecules
   
   1. Selectins- transient on/off binding
      
      1. L-selectin
      2. bind carbohydrates on endothelial interaction
   2. mucin-like vascular addressins
      
      1. CD34
      2. bind to L-selectin initiate Leukocyte-endothelial interaction
   3. integrins- promote strong adhesion
      
      1. LFA-1
      2. bind to CAM and extracellular matrix
   4. some immunoglobulin superfamily members
      
      1. CD2
         
         1. Tcells
      2. ICAM-1
         
         1. vascular
      3. ICAM2
         
         1. endothelium

Question 4

Describe the signals necessary for ativation of naive T cell. diagram and draw structures involved

Answer 4

1. co-stimulatory signal and specific signal
   
   1. normal activation
2. specific signal alone
   
   1. T cell recognizes self antigen but is missing the costimulatory
   2. Tcell-> anergic
      
      1. does not work anymore and eventually comits to apoptosis
   3. concept of peripheral tolerance
3. costimulatory signal alone
   1.

Question 5

danger model

Answer 5

theory of how the immune system works, based on the idea that the immune system does not distinguish between self and non-self, but rather between things that might cuase damage and thigs that will not

Question 6

list the CAM, ligand and locations

Answer 6

cell adhesion molecules are expressed in lymphocytes, APCs, endothelial lining.

the idea is to have trainsient interactions then strong interactions

1. naive T cell
   
   1. L-selectin
   2. CCR7
   3. LFA-1
   4. CD2
2. APC
   
   1. LFA-3
   2. ICAM-1
   3. ICAM2
   4. DC-SIGN
3. endothelium-lymph node, effector site
   
   1. CD34 and GlyCAM
   2. CCL21
   3. ICAM-1

Question 7

Describe the T cell signaling pathways initiated through TCR/coreceptor and Cd28

Question 8

what are the different families for chemokines, cyotkines and interferons

Answer 8

This signal determines what the cell will be doing (

1. type 1 cytokine receptor
   
   1. jakstat
2. type2 cytokine receptor
   
   1. jak-stat
3. IL-1
   
   1. globular domains
   2. signals through IRAK
   3. for innate immunity, act as PRR’s
   4. seen in inflamasomes
4. gprotein
   
   1. chemokines
   2. direct the cell where to go
5. common gamma chain
6. common beta chain
7. IL-6 receptor family

Question 9

describe the affect of superantigens on T/B cells

Answer 9

The superantigen forces the TCR-MHC complex to interaction.

1. signal 1 initiates, but most of the time signal 2 is not started.
   
   1. This stimulates a massive amount of T cells and releases TONS of cytokines.
   2. systemic inflammation

for B cells the membrane bound antibodies become crosslinked and the b cell will not become very functional.

1. because there was no T cell involved in the activation the B cell will not respond efficiently
2. polyclonal activation, instead of monoclonal

The cell could eventually experience superantigen-induced cell death.

wasted energy, activated T/B cells looking for something that isn’t there. also, turning on something that wasn’t supposed to be turned on: autoimmune disease

Question 10

describe/diagram the migration and homing of naive T cells into the HEV

Answer 10

migration and homing- leading to diapedesis

1. refering to the movement of naive T cells into secondary lymphoid tisses or sites of infection/inflammation
2. process
   
   1. the T cell marker, L selectin, interacts with the Cd34 and GlyCAM on the endothelium,
      
      1. this generates a rolling action. The interactions are transient and allows the slowing down of the cell.
   2. CCR7, on naive T cell, interacts with CCL21 on endothelium.
      
      1. induces LFA-1
   3. LFA-1 interacts with ICAM-1
      
      1. This is the strong bond between the naive T cell and the endothelium, tells the cell to stop rolling
      2. and induces intracellular responses that induce the process of Diapedesis.

Question 11

what are the phases in Tcell response?

Answer 11

two phases

1. phase 1
   
   1. activation
   2. expansion
   3. differentiation of naive T cells to effector T cells
2. phase 2
   
   1. execution of the T cell effector functiona

Question 12

define the activation of T cells, location this occurs.

what is happening in the locations:

1. lymph nodes
2. spleen
3. adenoids, BALT
4. GALT, peyers patch

Answer 12

1. naive T cell activation occurs in the secondary lymphoid organ
   
   1. spleen, lymphnode…
2. process
   
   1. APC
      
      1. APC could run to the draining lymph node and present to the Ag
      2. could have a T cell enter that recognizes some thing on the APC
   2. T cells that recognize
      
      1. proliferate
      2. differentiate
3. location is important
   
   1. Lymph node
      
      1. processeced by DCs and MO
         
         1. lymph nodes draining infected or inflamed area is a depot of processed antigens on DC and MOs
   2. spleen
      
      1. blood infections
   3. adenoids, tonsils, BALT
      
      1. respiratory infections
   4. peyers patch, GALT
      
      1. gastointestinal infections

Question 13

Describe the Tcell-APC interaction with CAMs dissociate between initial and strong interactions

Answer 13

CAMs

1. initital transient binding between T cells and APCs
   
   1. mediated by integrins and members of Ig superfamily
      
      1. LFA-1 on the T cell interacts with ICAM-1/2 on the APC
      2. LFA-1 on the APC interacts with the ICAM-3 on the Tcell
2. stong adhesion is mediated by
   
   1. CD2 on the T cell interact with LFA-3 on APCs
   2. ICAM-3 on Tcells interact with DC-SIGN

Question 14

Describe/diagram the TCR APC interaction and activation of trasnscription factors

Answer 14

T cell signaling pathway is initiated through two signals

1. TVR/Coreceptor-signal 1
   
   1. The CD3( epsilon/gamma and epsilon/delta) and zeta chains all contain immunoreceptor Tyrosine Activating Motifs(ITAMs).
   2. The CD4 has a bound Lck, phosphorylating motif, which becomes unbound, by CD45, when MHC-TCR interaction.
   3. The CD4 communicates with the B2domain of the MHC2 domain, bringing Lck close enough to phophorylate the ITAMs of the TCR
   4. ZAP70 is recruited to the ITAM SH2 domains (i think the zeta comonents). ZAP70 becomes phosphorylated by ZAP70
   5. with ZAP 70 near the surface, a scafold forms and is phosphorylated by ZAP 70 (LAT, GLD, SLIP76)
2. CD28stimulation-signal 2
   
   1. interaction between CD28 and CD80 leads to the phosphorylation of CD80s intracellular domain and the reqruitment of PI3K
   2. PI3K phosphorylates membrane bound PIP2 to become PIP3
   3. PIP3 recruites
      
      1. PLC-gamma bringing to the scafold, formed in signal 1.
      2. then,PIP3, reqruites a phosphrylating agent for PLC-y fully activating PLC-y
   4. PLC-y cleaves PIP3->IP3 and DAG
      
      1. DAG/IP3 go down different cascades to activate the NFkB, NFAT and AP-1 gene expression
   5. NFkB, NFAT and AP-1 gene expression lead to the effector T cell status
      
      1. division
      2. proliferation
      3. differentiation

Question 15

What is the signaling station and molecule responsible for signal three?

Answer 15

Jak=cytoplasmic Y-Kinases that mediate cytokine receptor signaling

STAT=signal transducers and activators of transcription= latent cytoplasmic transcription factors that become activated upon recruitment to an activated receptor complex.

JAK-STAT does the following

1. receives a signal from the cytokine ligand
2. JAK autophosphorylates and then phosphorylates tyrosine residues
   
   1. activated receptors
3. reqruiting STAT
4. STAT becomes phosphorylated and dimerizes
5. Dimerized STAT translocates into the nucelus and activates gene expression

Question 16

describe and diagram the process expressing important cytokine receptors.

What is the source of the ligands? What is the difference between the CD4 and CD8?

Answer 16

Tcells-and IL-2

1. naive cells
   
   1. express gamm/beta subunit of the cytokine receptors.
2. Activated T cell
   
   1. activated T cells are undergoing gene expression and one of those genes generates the necessary componenet to increase the affinity for IL-2.
   2. also, gene expression of IL-2 starts
3. IL-2
   
   1. IL-2 receptor now as a whole (gamma/beta/alpha) generates a high affinity for IL-2.
   2. The autocrine secretion of IL-2 stimulates the IL-2R and starts cascade for cell proliferation

While the Tcells are proliferating from autocrine signals, the APC’s secrete specific cytokines for differentiation.

1. signal 3
   
   1. cytokine panels that deliver signal 3 influence effector function of the CD4 cells
   2. induce CD8 T cell differentiation to CTLs

Question 17

How can the 3 signals be used for medical treatment?

Answer 17

immunosuppressive drugs

1. used to block unwanted expansion of T cells
   
   1. cyclosporinA
      
      1. disrupts TCR signaling
   2. tacrolimus (FK506)
      
      1. disrupts TCR signalin
   3. rapamycin
      
      1. inhibits signaling downstream IL2R