Week 14 Flashcards by Dean Matthews

SHP-1 and SHP-2

non-receptor tyrosine phosphatases that dephosphorylize tyrosine and terminate signaling

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IL-12

Activates NK cells. Induces differentiation of CD4+ cells into Th1 cells.

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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

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MSH2 / UNG double KO

Almost no A:T mutations. No CSR.

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UNG deficiency

mainly transition mutations at G:C to A:T

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MMR / MSH2 deficiency

Reduced mutations at A:T base repair

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Chromatin modifications near DSBs

gamma-H2AX

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Conrad Waddington

Epigenetic Landscape showing how genes affect cell development decision and instruct differential potential

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histone modification responsible for rapid response of inflammatory genes

H3.3S31ph delineating gene bodies, H3.3S28ph delineating promoters and enhancers

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Histone types

H3, H4, H2A, H2B and H1

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What enzymes modify histones with acetylation?

histone acetyltransferases (HATs) and histone deacetylase (HDACs)

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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

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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

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Through what protein are integrins linked to the cyoskeleton?

talin

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Weibel–Palade bodies

Pre-formed granules in endothelial cells that contain P-selectin. Released to cell surface in response to TNFa.

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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.

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P- and E-selectin ligands

sulfated sialyl-LewisX on neutrophils

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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.

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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