Week 14 Flashcards
SHP-1 and SHP-2
non-receptor tyrosine phosphatases that dephosphorylize tyrosine and terminate signaling
IL-12
Activates NK cells. Induces differentiation of CD4+ cells into Th1 cells.
Two phases of AID SHM
Phase one is the deamination of C to a U that is not corrected by DNA repair mechanisms - this is later paved over as a T in later progeny.
Phase two is deamination of C to a U that is corrected by either UNG or MSH2/6
MSH2 / UNG double KO
Almost no A:T mutations. No CSR.
UNG deficiency
mainly transition mutations at G:C to A:T
MMR / MSH2 deficiency
Reduced mutations at A:T base repair
Chromatin modifications near DSBs
gamma-H2AX
Conrad Waddington
Epigenetic Landscape showing how genes affect cell development decision and instruct differential potential
histone modification responsible for rapid response of inflammatory genes
H3.3S31ph delineating gene bodies, H3.3S28ph delineating promoters and enhancers
Histone types
H3, H4, H2A, H2B and H1
What enzymes modify histones with acetylation?
histone acetyltransferases (HATs) and histone deacetylase (HDACs)
selectins
membrane glycoproteins with a distal lectin-like domain that binds specific carbohydrate groups. Members of this family are induced on activated endothelium and initiate endothelium–leukocyte interactions by binding to fucosylated oligosaccharide ligands on passing leukocytes
leukocyte integrins important for extravasation
LFA-1 (L:2, also known as CD11a:CD18) and CR3 (M:2, complement receptor type 3, also known as CD11b:CD18 or Mac-1)
Both bind to ICAM-1 and ICAM-2
Through what protein are integrins linked to the cyoskeleton?
talin
Weibel–Palade bodies
Pre-formed granules in endothelial cells that contain P-selectin. Released to cell surface in response to TNFa.
Epithelial cell response to TNFa
release of P-selectin from Weibel–Palade bodies, followed by mRNA transcription of E-selectin. Mostly E-selectin expressed after 2 hours.
P- and E-selectin ligands
sulfated sialyl-LewisX on neutrophils
What allows circulating leukocytes to interact with the endothelium?
Inflammation-induced vasodialation allows for decreased blood flow, allowing the luekocytes to slow down enough to interact with the endothelium.
What induces P-selectin release from endothelial cells?
leukotriene B4, C5a, histamine
Also LPS and TNFa, which also cause E-selectin transcription
How are neutrophils able to roll along endothelium under such high shear from blood flow?
They use ‘slings’, which are long extensions of plasma membrane that wrap up around the rolling cell and slow it down.
Molecular interactions of extravasation
- P/E-selectin and sialyl-LewisX
- LFA-1/CR3 and ICAM1/2
- Extravasation by the interaction of CD31(PECAM) on both endothelial cells and leukocytes - enzymes break down basement membrane
- migration under the influence of chemokines
How do chemokines induce chemotaxis?
They bind to proteoglycans in the extracellular matrix and on endothelial surfaces, making a matrix-associated gradient to the infection.
Acute-phase proteins
serum amyloid, CRP, fibrinogen, MBL, SP-a/D
First protein that a newly-synthesized MHC-I binds to
calnexin
Differences between terminal amino acids of peptides in MHCI or MHCII
MHCI is closed, so it has constant terminal amino acids. MHCII can have variable terminal amino acids
Types of MHCII superantigens
Bacterial superantigens – staphylococcal enterotoxin B and A (SEB and SEA), toxic shock syndrome toxin-1 (TSST-1)
-Viral superantigens (vSAG): endogenous mammary tumor viruses
Differences between bacterial and viral superantigens
viral antigens are transmembrane
Class II MHC peptides that bind to groove before presented peptide
Starts with generaic ER chaperones, calnexin, BiP and the Invariant chain (Ii)
Ii targets MHCII to the endosome.
Ii is cleaved to CLIP - pH dependent
HLA-DM releases CLIP.
Which CD3s associate with the lipid membrane in absence of activation?
CD3e, CD3z
Lipid gradients for chemotaxis
PIP3 in front, generated by GPCR activation, PIP2 concentrated at tail end
How does ligand binding induce TCR activation?
Phosphatase exclusion
TCR conformational change
The kinetic proofreading model
Mechanotransduction
2) How does receptor activation induce downstream signaling?
Liquid-ordered signaling microclusters
Lipid second messengers
Calcium signaling
How does interfacial architecture influence T cell activation and effector responses?
Microvilli and ligand search
Actin dynamics and mechanotransduction
Mechanopotentiation of effector responses
Important molecules that bind to activated CD28
SLP76, PI3K, VAV3, Lck
Which type of catabolism suits proliferating cells?
Aerobic glycolysis
How do cancers keep proliferating?
By finding a way to block terminal differentiation - expression of transcription factors, mutation of chromatin-remodeling enzymes, and changes in cellular metabolism
Two molecules other than CD25 highly upregulated on Tregs
CD5, CTLA-4
Differences between birth- and death-limited selection in the GC
Positively selected cells divide more times if they receive stronger T cell signals (birth-driven selection), which can have a strong exponential effect•
Death-limited selection is strong against nonsense mutations in the DZ (BCR driven); death based on affinity is harder to demonstrate
Histone methylation enzyme
histone methyltransferase (HMT) - methlates H3 and H4
Active markers of histone methylation
H3K4, H3K36, and H3K79
Repressive markers of histone modification associated with silencing and condensed chromatin
H3K9, H3K27, and H4K20
Histone acetylation
regulated by the balance between histone acetyltransferases (HATs) and histone deacetylases (HDACs). Acetylation can reduce the positive charge of the lysine residues, which will then inhibit the binding between histone tails and negatively charged DNA, leaving the underlying DNA exposed. Therefore, histone acetylation is usually considered as an active histone mark
nucleosome
basic unit of chromatin, with ∼147 base pairs of DNA wrapped around a protein octamer, containing two copies each of “core” histones H2A, H2B, H3, and H4
Role of ERGIC in MHCI peptide loading
intracellular retention of unstable, empty, and suboptimally loaded dimers that are prevented from reaching the plasma membrane
Which cytocolic nucleic acid sensor can directly recruit caspase-1?
NLRC4
