T Cell Polariz & Cytokines (1/9) Flashcards
What are 3 ways that naive T cells get activated?
- MHCI or II present Ag’s to CD8 or CD4 T-cells (required for memory T cell activation)
- APC co-receptors i.e. CD80/86 activate T-cell CD28 (required to prevent anergy of T cells)
- Cytokines promote T-cell polarization i.e. Th1, 2, 17
What are cytokines?
Small, secreted & glycocylated proteins that bind to cell receptors with high affinity
Expression of both cytokines & their receptors is tightly regulated
Receptors determine what type of response you get to cytokine
What are the 2 most important families of cytokines?
TNF (TNF-alpha – a trimer, LT-alpha/beta, FasL, CD40L)
4 helpix bundle family (mostly interleukins – monomer with 2 faces)
How do cytokines act?
Transient responses on target cells- can be autocrine, paracrine or endocrine (i.e. IL1,6, and TNF-alpha levels found in blood)
Can exhibit pleiotropism, redundancy, synergy, or antagonism
What are examples of the 4 general properties of cytokines: pleiotropism, redundancy, synergy, and antagonism
What is the signalling pathway by which cytokines signal?
JAK-STAT pathway
JAKs=the receptor associated tyrosine kinase
STAT=the TF that they activate
Allows an extracellular signal to make a response inside the cell
Through which pathway do TNF receptors signal? 2 options
TRADD to FADD to caspase 8 –> cell death
TRADD to RIP to TRAF 2 –> gene expression
Both ultimately lead to NF-kappaB
In addition to cytokines, what are other innate inflammatory responses?
Antimicrobials, inflammatory lipids, inflammatory cytokines/chemokines, cellular phase: immune sentinels
What are the 2 main sentinel cells? Which is most important sentinel cell?
Macrophages and DC
Macrophages are more important bc there are more of them & they stay at the site of infection (DC to lymph node)
What are the types of innate immune receptors?
Signalling receptors: TLRs, RIG-1 like, NLRs, Dectin-1 for C-type lectins
Phagocytic receptors: Complement receptors, C type lectin receptors, scavenger receptors, secreted receptors i.e. collectins, complement, pentraxins (CRP)
They all detect microbes
What do activated macrophages do?
Secrete chemokines to direct the ensuing response
Examples:
IL-1 beta: requires both TLR activation & activation of inflammasome;
TNF-alpha: increases vascular permeability
Also: IL-6, CXCL8, IL-12
Final result = fever, shock, protein production etc
Why does the clotting system also get activated during local infection?
So that an infection stays local
Chemokines & cytokines –> dilation of local small blood vessels –> stick to periphery due to increased expression of adhesion molecules –> leukocytes extravasate at site of infection –> clotting in microvessels
What happens during systemic infections?
Macrophages make interferons during systemic viral infection. Interferon activation –> activation of liver –> CRP/complement, bone marrow activation –> neutrophil mobilization/phagocytosis, hypothalamus/fat/muscle to increase body temp, DC to lymph node/activate Ag specific T cells
How can we model sepsis?
Inject LPS, which leads to secretion of chemokines & macrophage activation via IFN-gamma
What is the role of the liver in innate immunity?
When macrophages produce IL-6, hepatocytes start synthesizing CRP (which opsonizes) and other proteins
Also makes hepcidin, a Fe hormone that causes anemia of chronic disease (the idea is that limiting Fe makes it harder for bacteria to live, bc they require it to survive)
What are the T cell subsets that different cytokines specify?
5 cell fates: naive CD8 or naive CD4, which can become Th1, Th2, Th17, or iTreg
They all do different functions: each has its signature cytokine
What regulates this: MHCI v MHCII, coreceptors (CD28, CD80, CD86), cytokines, chemokines, local factors
