Module 7: T cell Activation

Question 1

Why is costimulation so important?

Answer 1

1) Costimulation produces a more pronounced response in T cells
2) Without costimulators, T cells enter a state of anergy or die by apoptosis

Question 2

Describe the role of CD28:B7 costimulatory interactions

Answer 2

1) CD28 is a positive costimulatory receptor on T cells which binds B7 found on APCs
2) On resting APCs, B7 is absent/low
3) Microbial products binding to TLRs and cytokines (IFN-γ) released during infection upregulates B7 expression
4) Results in activation of T cells (with antigen recognition)

Question 3

Why is having low levels of B7 on resting APCs important?

Answer 3

1) Mediate peripheral tolerance
2) When T cells recognize self-antigens, they do not receive the costimulatory interaction required (enter anergic state)
3) Important for Treg maintenance and generation

Question 4

Describe the role of CD40L:CD40 costimulatory interactions

Answer 4

1) CD40L is expressed activated T cells and binds CD40 expressed on APCs
2) Binding enhances B7 expression on APCs (feedback loop that amplifies T cell responses)

Question 5

Why are DCs the most potent activators of T cells?

Answer 5

They express the highest levels of costimulators

Question 6

Describe the role of ICOS:ICOS-L costimulatory interactions

Answer 6

1) ICOS is a positive costimulatory receptor on T cells which binds ICOS-L expressed on DCs and B cells
2) Binding induces development and activation of follicular helper T cells
3) Follicular helper T cells provide activating signals to B cells in germinal reaction centers

Question 7

Which costimulatory receptors are inhibiting?

Answer 7

CTLA-4, PD-1, BTLA - involved in tolerance

Question 8

Which costimulatory receptors are activating?

Answer 8

CD28 and ICOS

Question 9

What are the 3 actions of cytokines?

Answer 9

1) Autocrine
2) Paracrine
3) Endocrine

Question 10

What are the 5 cytokine functions?

Answer 10

1) Pleiotropy
2) Cascade induction
3) Redundancy
4) Synergy
5) Antagonism

Question 11

What are the 4 mechanisms of cytokine specificity?

Answer 11

1) Proximity to target cell (concentration)
2) Activated (receptive) cell population
3) Regulation of cytokine receptors
4) Associated cell-cell interactions

Question 12

IL-2

Answer 12

1) Produced by Th (TH0 or TH1) and Tc cells
2) Targets Th, Tc cells, and NKCs
3) Paracrine or autocrine release
4) Most important cytokine produced early after activation
5) Maintenance of Tregs, proliferation of stimulated T cells, growth of T cells, enhances Tc and NKC activation

Question 13

IL-15

Answer 13

1) Produced by monocytes, macrophages, DCs, BM stromal cells, epithelial/endothelial/fibroblasts (on surface or released)
2) Targets Th, Tc cells, NKCs
3) Recruits T cell precursors to thymus, induces T cell proliferation, enhances Tc and NKC activation

Question 14

What are the 6 cytokine/receptor families?

Answer 14

1) Interleukin-1 (IL-1) family
2) Class I (hematopoietin) cytokine family
3) Class II (interferon) cytokine family
4) Tumor necrosis factor (TNF) family
5) Interleukin-17 (IL-17) family
6) Chemokines

Question 15

Which cytokine/receptor families signal via the MAPK/NF-kB pathway?

Answer 15

IL-1, IL-17, TNF family

Question 16

Which cytokine/receptor families signal via the JAK/STAT pathway?

Answer 16

Class I (hematopoietin) and Class II (interferon) cytokine family

Question 17

Which pathway do chemokines signal?

Answer 17

Signal via G-coupled receptors

Question 18

What are some members of the IL-1 family

Answer 18

Inflammatory mediators

Question 19

What are some members of the Class II cytokine family

Answer 19

IL-2,4,7,15,21

Question 20

Describe TNF family functions

Answer 20

Soluble or membrane bound, involved in immune development, effector functions, and homeostasis

Question 21

Describe IL-17 family functions

Answer 21

Proinflammatory, promote neutrophil accumulation and activation

Question 22

Explain the steps of the JAK/STAT pathway

Answer 22

1) Binding of cytokines results in receptor dimerization
2) Autophosphorylation of JAK and receptors on tyrosine residues
3) Phosphorylated tyrosine residues act as docking sites for STATs
4) STATs are phosphorylated, activation results in dimerization
5) STAT dimers translocate to the nucleus and induce gene transcription

Question 23

What are the different kinds of cytokine antagonists

Answer 23

1) Cytokine analogues that bind receptors but do not induce signaling
2) Soluble receptors that bind the cytokine to prevent binding to true receptor
3) Truncated versions of chemokines
4) Cytokines that affect production of other cytokines

Question 24

What are some examples of cytokine antagonists that act directly on receptors?

Answer 24

IL-1ra (IL-1 receptor antagonist)

Question 25

What are some examples of cytokine antagonists that are soluble receptors?

Answer 25

sIL-1Rs (soluble IL-1 receptors), sTNF-Rs (soluble TNF alpha receptors)

Question 26

What are some cytokines that are antagonists?

Answer 26

IL-4, IL-10, and TGF-β

Question 27

How do Th cells provide help to CTLs?

Answer 27

Th1 cells help through CD40L and IL-2 interactions which induces proliferation and cytotoxic activity

Question 28

IL-4

Answer 28

1) Produced by TH2 cells, basophils, minor subsets of CD4+ T cells
2) Targets B and T cells, mast cells
3) Activates B cells, induces IgE production, upregulates class II cytokine receptors on B cells, stimulates growth in mast cells, phagocytic activity in macrophages

Question 29

IL-5

Answer 29

1) Produced by TH2 cells
2) Targets activated B cells and eosinophils
3) Induces B cell proliferation/differentiation, eosinophil growth, class switch to IgA

Question 30

TGFβ

Answer 30

1) Produced by platelets, macrophages, lymphocytes
2) Targets monocytes/macrophages, lymphocytes/activated B cells, epithelial/endothelial
3) Inhibits proliferation and inflammation, promotes wound healing, class switch to IgA

Question 31

IL-12

Answer 31

1) Produced by macrophages and B cells
2) Targets activated Tc cells, NKCs, TH1
3) Stimulates Th1, synergistic with IL-2 for CTL activation, NKC proliferation, γ-IFN release

Question 32

IL-10

Answer 32

1) Produced by TH2
2) Targets APCs and macrophages
3) Suppresses cytokine production and downregulates MHC II (except in B cells)