T Cell Effectors

Question 1

Main Function of Th1 Cells

Answer 1

Macrophage Activation

• Macrophages have receptors for IFN-gamma and CD40 on membrane; CD40L of Th1 T cell binds CD40 and IFN-gamma made by Th1 T cell binds macrophage receptor
• Response = inc prod of ROS and NO to kill microbes better; macrophages secrete TNF, IL-1 and IL-12; inc expression of MHC and stimulators (B7) to uplift more T cells
• IL-12 then stimulate T cells and NK cells to make more IFN-gamma (CYCLE)

Question 2

2 Main Functions of Th2 Cells

Answer 2

1- Eosinophil activation

- Parasites too large to be phagocytosed
- Thf cells (related to Th1) secrete IL-4 —> IgE antibodies coat parasite
- Secrete IL-5 which activate eosinophils to secrete their toxic granules AND recruit mast cells
- Secrete IL-13 which inc peristalsis and mucus secretion to get parasite out of GI tract

2- Inhibit Classical Macrophage Activation/ Stimulate Alternative Macrophage Activation

- IL-4 and IL-13
- Alternative path —> macrophages recruit fibroblasts for collagen/scar formation and tissue repair; ANTI-INFLAMMATORY (macrophages release TGF-beta and IL-10)

Question 3

Main Function of Th17 Cells

Answer 3

• Defense against bacterial or fungal infections (extracellular)
  
  • IL-17 stimulates production of chemokine —> recruit leukocytes
  • IL-17 stimulates production of defensins (anti-microbial substances - endogenous abx)
  • IL-22 helps maintain integrity of epithelial barriers

Question 4

Cytokines/Targets of Th1 Cells

Answer 4

IFN - gamma

macrophages (classical activation - inc killing ability along w/ CD40L)

Question 5

Cytokines/Targets of Th2 Cells

Answer 5

IL-4 IL-5 IL-13

eosinophils

(activate them and switch B cells to IgE - IgE coats parasites)

Question 6

Cytokines/Targets of Th17 Cells

Answer 6

IL-17 IL-22

neutrophils
stimulate acute inflammation and maintain epithelial barrier

Question 7

Development of Th1 Cells

Answer 7

Exposure to IL-12 and IFN-gamma from dendritic cells and NK cells AND antigen stimulation —> transcription factors activated (T-bet, STAT1, STAT2)—> differentiation

Question 8

Development of Th2 Cells

Answer 8

Exposure to IL-4 from mast cells, other tissue cells or T cells at site of infection AND antigen stimulation —> transcription factors activated (GATA-3 and Stat6) —> differentiation

Question 9

Development of Th17 Cells

Answer 9

• Exposure to cytokines (IL-1 IL-6 IL-23) secreted by dendritic cells in response to fungal/bacterial infection —> transcription factor activation (RORgammat and stat3)
  
  • Dendritic cells release these cytokines when they recognize fungal glycans and bacterial peptidoglycans and lipopeptides
• When TGF-beta is in combo w/ IL-1 and IL-6 it helps promote Th17 differentiation

Question 10

Roles of TGF-beta (2)

Answer 10

When TGF-beta is in combo w/ IL-1 and IL-6 it helps promote Th17 differentiation

INHIBITS T cell activation and causes differentiation of regulatory T cells

Question 11

How do CD8+ Effector Cells Work?

Answer 11

• Bind antigen —> activation —> signaling —> exocytosis of granule contents into synapse b/n T cell and infected cell; kill via granule proteins getting into infected cells
• 2 Main Types of Granule Proteins
  - 1- Granzyme B - cleaves caspases in cytosol of target cells —> apoptosis
  - 2- Perforin - polymerizes; disrupts plasma membrane and endosomal membranes of target cell in order to facilitate granzymes getting into cytosol —> apoptosis
• Can also induce apoptosis w/o granules; activated CTLs express Fas ligand which binds Fas on target cell —> activates capsizes in target cell —> apoptosis
• During apoptosis the microbes DNA is also broken down
• CD8+ cell only needs to make contact for few min
• CD8+ cells also produce IFN-gamma to activate macrophages

Question 12

CD4+ and CD8+ Cooperation (3 Ways)

Answer 12

1- If ingested microbe, first CD4+ will release IFN-gamma to activate macrophages/enhance macrophage killing BUT if microbe escapes from vesicle —> cytosol than CD8+ effectors now needed

CD4+ cells can help in CD4+ activation…

2- CD4+ cells have CD40 ligand which binds CD40 of APCs to make them more effective at presenting to CD8+ cells (“licensing of APCs”)

3- Secrete cytokines —> differentiation of CD8+ cells

Question 13

6 Examples of Microbe Resistance to T Cell Action

Answer 13

• Inhibit phagosome/lysosome fusion - mycobacteria
• Interfere w/ TAP transport - HSV (Herpes Simplex Virus)
• Inhibit proteasomal activity in ER - CMV or Epstein Barr Virus
• Remove class I MHC molecules from ER - CMV
• Inhibit macrophage or dendritic cell activation/produce IL-10 - Epstein Barr Virus
• Block cytokine activation of effector cells (by making the receptors soluble) - Pox

Question 14

T Cell Exhaustion

Answer 14

• If antigen persist, chronic infection
  
  • T cells start to express inhibitory receptors (PD-1 which binds PD-1Ligand & CTLA-4 which binds B7)
  • T cells no longer secrete cytokines, kill target cells or proliferate as much (NO RESPONSE)

Question 15

When are co-stimulators needed?

Answer 15

• 1- APC presents to naive T cell in secondary lymphoid organs—> proliferation and differentiation
  
  • Require co-stimulator (CD28-B7)
• 2- APC presents to effector T cells at the site of infection —> effector mechanisms/killing/elimination
  
  • Co-stimulator no longer needed