Module 7: T cell Activation Flashcards
Why is costimulation so important?
1) Costimulation produces a more pronounced response in T cells
2) Without costimulators, T cells enter a state of anergy or die by apoptosis
Describe the role of CD28:B7 costimulatory interactions
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)
Why is having low levels of B7 on resting APCs important?
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
Describe the role of CD40L:CD40 costimulatory interactions
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)
Why are DCs the most potent activators of T cells?
They express the highest levels of costimulators
Describe the role of ICOS:ICOS-L costimulatory interactions
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
Which costimulatory receptors are inhibiting?
CTLA-4, PD-1, BTLA - involved in tolerance
Which costimulatory receptors are activating?
CD28 and ICOS
What are the 3 actions of cytokines?
1) Autocrine
2) Paracrine
3) Endocrine
What are the 5 cytokine functions?
1) Pleiotropy
2) Cascade induction
3) Redundancy
4) Synergy
5) Antagonism
What are the 4 mechanisms of cytokine specificity?
1) Proximity to target cell (concentration)
2) Activated (receptive) cell population
3) Regulation of cytokine receptors
4) Associated cell-cell interactions
IL-2
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
IL-15
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
What are the 6 cytokine/receptor families?
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
Which cytokine/receptor families signal via the MAPK/NF-kB pathway?
IL-1, IL-17, TNF family
Which cytokine/receptor families signal via the JAK/STAT pathway?
Class I (hematopoietin) and Class II (interferon) cytokine family
Which pathway do chemokines signal?
Signal via G-coupled receptors
What are some members of the IL-1 family
Inflammatory mediators
What are some members of the Class II cytokine family
IL-2,4,7,15,21
Describe TNF family functions
Soluble or membrane bound, involved in immune development, effector functions, and homeostasis
Describe IL-17 family functions
Proinflammatory, promote neutrophil accumulation and activation
Explain the steps of the JAK/STAT pathway
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
What are the different kinds of cytokine antagonists
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
What are some examples of cytokine antagonists that act directly on receptors?
IL-1ra (IL-1 receptor antagonist)
