Lecture 26 Flashcards
What does negative regulation involve?
Receptors, mechanisms, and cell types (Tregs)
How do Tregs dampen effect T cell responses (post infection)
Tregs release inhibitory cytokines
Pathways of Apoptosis
Intrinsic and Extrinsic pathways
What is the Intrinsic pathway of apoptosis
Death by neglect
T cell gets activated (signal 1 and 2)–>produce cytokines with transient receptors (IL2Ralpha) (impermanent)–>eventually signaling stops through these receptors–>lack of signaling = absence of survival signal–>apoptosis
What is the Extrinsic pathway of apoptosis
Rely on external source to initiate apoptosis
Triggered by Fas-FasL
involves CTLs
What causes activation on APC and T cells
B7.1 and B7.2 binding on antigen presenting cells = activation
CD28 binding on T cells = activation
What interaction causes negative regulation
CTLA4 interacting with B7.1 and B7.2 to block T cell activation
Examples of an inhibitory/regulatory receptors
CTLA4 and PD1
What receptor is expressed on Naive T cells
CD28
What receptors do T cells express 24 hours activation
CD28 AND CTLA-4 receptors (regulatory function to prevent overexpression of T cells)
Where is CTLA-4 found before post translational modification
Intracellularly
Where is CTLA-4 found after post translational modification
Phosphorylation allows CTLA-4 to be expressed on cell surface
Consequence of negative regulation by CTLA-4
Inhibit proliferation of T cells
Where is PD-1 expressed
On activated T cells
What does PD-1 bind to
PDL-1 (expressed on many cells) and PDL-2 (on APC during inflammation)
Consequence of PD-1 signaling
Downregulation of T cell activation
What is PD-1 a marker of
T cell exhaustion (apparent in chronic disease)
What cytokines are associated with iTreg’s Signal 3
IL-2 and TGFbeta
What effector cytokines are associated with iTreg
IL-10 and TGFbeta (anti-inflammatory cytokines)
What master transcriptional regulator is associated with iTregs
FoxP3
Main action of iTreg
iTregs suppress immune responses to maintain immune tolerance to self antigens (prevent autoimmunity)
What are the Treg subsets
Natural Tregs and Induced (adaptive) Tregs
Where are natural Tregs derived
Thymus-derived
How are natural Tregs selected
Selected for high affinity for self peptides to dampen immune response to them
Which receptors do natural Tregs express
TCR, CD4, IL2Ralpha, CTLA-4
Also express FoxP3 (master transcriptional regulator)
Where do induced Tregs/iTregs arise
In periphery from CD4+ T cells
What receptors do iTregs express
TCR, CD4, IL2Ralpha, and CTLA-4
Also express FoxP3 but some exceptions
iTreg signaling pathway
Naive CD4+ T cell–>IL-2 and TGFbeta (signal 3)–>STAT 5 (transcription factor)–>FoxP3 (master transcriptional regulator)–>IL-10 and TGFbeta secretion
Action of Tregs (both natural and induced)
1) Secrete IL-10 and TGF-beta
2) Represses other immune cells, mainly T cells
How do Tregs cells negatively regulate immune responses
1) Deplete local area of stimulating cytokines (express IL2Ralpha (CD25) chain–>sequester IL-2)
2) B7 sequestration by CTLA-4
3) Produce immunosuppressive cytokines (IL-10 and TGFbeta)
4) Directly kill T cells through granzymes and metabolic disruption
Consequences of B7 sequestration by CTLA-4
1) Inhibits APC activity by reducing co-stimulatory molecule expression and pro-inflammatory cytokine secretion
2) Reduce T cell differentiation and activation
Action of IL-10 (Treg anti-inflammatory cytokine)
Inhibits production of TH1 and TH17 cytokines
Action of TGFbeta (Treg anti-inflammatory cytokine)
Inhibits T cell proliferation and inhibit the development and function of TH1 and TH2
