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)
How do levels of TNF determine the biological response?
What are the biological respsonses of TNF?
Low levels –> local inflammation (leukocyte activation, ET cell adhesion)
Moderate –> systemic effects (brain- fever, liver - acute phase proteins, bone marrow-leukocytes)
High –> septic shock (low cardiac output, low resistance of BV, hypoglycemia)
Remember that TNF is more rapid & transient than IL-1beta (which requires 2 signals)
What are the signals that activated DC make to direct polarization of CD4 cells into effector cells?
3 signals:
- MHC II/TCR: ITAM motifs on NK cells recruit Zap-70 or Syk (kinases) –> Zap-70 leads to Ras/MapK pathway, cleavage of PIP2 –> IP3 + DAG –> NF-kappaB. Ultimately 3 TF’s, 3 including NF-kappaB, lead to gene activation –> IL-2, potent signal for rapid expansion of T cells
- CD80/86: requires a second activation signal
- IL-12 –> autocrine loop –> T cell expansion.
What are 2 drugs that interfere with IL-2 expression? What are they used for?
Cyclosporin A and Tacrolimus
Used for immune suppression bc they block calcineurin, a downstream enzyme that is in the TCR pathway
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
What happens if you have an imbalance of Th1, Th2, and Th17 cells?
Too much Th1 (IL-12 promotes its development) –> diabetes, granulomas
Too much Th2 –> asthma, allergies
Too much Th17 (IL-23) –> destructive inflammation, autoimmunity
Feedback loops, apoptosis, restricting GF, induced cell death, etc. help achieve balance
What types of cells secrete chemokines?
ET cells, lymphocytes, neutrophils, epithelial cells, fibroblast/smooth muscle cells, monocytes, macrophages, platelets
What type of signals do chemokines act through
G protein coupled receptors
What are the 2 types of chemokines?
Homeostatic: allow immune structure to develop
Inflammatory: recruit cytokines to site of infection
