Mcb 150 Midterm #2 - T-Cells

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inbred strain

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product of repeat brother sister matings; homozygous at all loci

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syngenic

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genetically identical at all loci

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congenic

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mice are genetically identical except for a small genomic region

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MHC restriction

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APCs used for re-stimulation must have the same MHC as the original strain

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MHC

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major histocompatibility locus; complex locus encoding many genes related to antigen presentation

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MHC class I and II genes of humans

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Class I: A, B, and C
Class II: DP, DQ, Dr

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MHC class I and II genes of mice

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Class I: K, D, L
Class II: I-A, I-E

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Genetic polymorphism

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many alternative forms of the same gene or alleles are present in a population "normal variants"

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mutation

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an alteration in the sequence of a gene as compared to the sequence of the predominant allele in a population

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haplotype

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the set of genes within a complex locus which are inherited as a group because they are linked on a chromosome

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HLA

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human leukocyte antigens; can test a person's HLA type by testing their white blood cells for reactivity to a panel of anti-leukocyte antibodies

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Endogenous pathway

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antigens from the cytosol are presented on MHC I molecules to CD8 T-cells

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exogenous pathway

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antigens internalized through endocytosis or phagocytosis are presented on MHC II molecules to CD4 T-cells

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Process for finding which gene is mutated in RMA-S cells?

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1. Take RMA cells and isolate mRNA
2. Make cDNA library
3. transfect RMA-S with pools of cDNA
4. check for rescued MHC I

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TAP

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transporters associated with antigen processing

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which cells are considered the professional antigen presenting cells?

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1. B-cells
2. macrophages
3. dendritic cells

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how do viruses interfere with Class I MHC expression in order to escape killing by CTLs?

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1. herpes simplex virus protein ICP47 can selectively bind to TAP and inhibit the transfer of peptides into the ER
2. human cytomegalovirus (HCMV) encodes proteins that retain MHC I molecules in the ER preventing presentation on the cell surface

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invariant chain

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binds MHC II molecules in the ER; blocks the binding of peptides; cleaved in the endosome leaving CLIP still bound to the MHC II

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HLA-DM (H-2M in mice)

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binds to and stabilizes empty Class II molecules; releases CLIP and allows other peptides to bind allowing MHC II molecule to travel to the cell surface

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how do pathogens evade MHC II?

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1. adenovirus interferes with Class II upregulation in APCs
2. HIV interferes with Class II processing
3. intracellular leishmania and mycobacteria manipulate phagosomes to prevent antigen presentation

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MIIC

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compartment for MHC II

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cross-priming

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the loading of antigenic peptides derived from exogenous proteins onto MHC I molecules

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alloreactivity

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non-specific T-cell response to mismatched MHC (1-5% of all T-cells are reactive to a given MHC allele)

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SH2 domain

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src homology domain; binds to specific phosphotyrosine containing motifs in signaling molecules such as ITAMs and helps PTKs find targets and scaffolds assemble signaling complexes

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Lck and Fyn

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Src family kinases that phoshporylate ITAMS and ZAP-70 once it is recruited

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Zap-70

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binds to phosphorylated ITAMs on CD3 zeta chains and activates downstream signaling events

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LAT

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part of the complex that recruits PLC-gamma

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SLP-76

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part of the complex that recruits PLC-gamma

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GADS

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part of the complex that recruits PLC-gamma

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NFAT

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transcription factor in the Ca+2 release pathway

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cyclosporin

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immunosuppressant drug that blocks the activity of calcineurin

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FK506

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immunosuppressant drug that blocks the activity of calcineurin

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What is ras?

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a small G-protein

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what are nude mice defective in?

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transcription factor required for terminal epithelial differentiation - leads to no thymus

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what are scid mice deficient in?

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DNA PK (DNA protein kinase) -> no gene rearrangement

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which cells mediate positive selection?

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cortical epithelial cells

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which cells mediate negative selection?

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medullary epithelial cells and dendritic cells

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pre T-alpha

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common chain that pairs with TCRbeta

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when does TCR alpha rearrangement begin?

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at the double positive stage

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where does positive selection take place?

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occurs on cortical epithelial cells (thymic cortex)

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where does negative selection take place?

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at the cortico-medullary junction

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AND thymus mutation

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see no single positive CD8 T-cells in either the spleen or the thymus; recognizes pigeon cytochrome c

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OT-1 thymus mutation

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see no single positive CD4 T-cells in either the spleen or the thymus; recognizes ovalbumin

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how does a T-cell "decide" whether to express CD4 or CD8

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Depends on the MHC it has affinity for -> if it binds to MHC I becomes single positive CD8 T-cell; if it binds to MHC II, becomes single positive CD4 T-cell

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Aire

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a transcription factor who job is to drive expression of genes in the thymus so you can eliminate self-reactive peptides

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Low affinity for peptide-MHC

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Positive selection

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high affinity for peptide-MHC

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negative selection

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What happens after T-cells leave the thymus?

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Naive T-cells exit the thymus and enter the bloodstream. If they remain in the bloodstream, they will pass through the spleen. They can also enter lymph nodes by crossing the high endothelial venules. If the T-cells are not activated, they re-enter the bloodstream and start all over again

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Why are dendritic cells such good APC's?

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1. they express both MHC I and II
2. They start in the right place (tissues)
3. they end up in the right place (lymph node)
4. immature DCs are highly efficient at taking up antigens in the tissues
5. After maturation and migration, mature DCs present these antigens to T-cells in the lymph node.
6. They express co-stimulatory molecules

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Signal 1 without signal 2 leads to what?

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anergy

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Tregs

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regulatory T-cells (a 3rd mechanism of tolerance); CD4+CD25+ T-cells (express TCRalphabeta, produced in the thymus, necessary for maintenance of tolerance)

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FoxP3

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transcription factor required for Treg development

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TLR4

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recognizes LPS

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TL9

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CpG unmethylated DNA

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TLR5

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flagellin

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TLR1

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lipoproteins, peptidoglycan

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Th1

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produces IFN-gamma and IL-2

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Th2

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produces IL-4, IL-5, and IL-13

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Th17

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produces IL-17, IL-21, and IL-22

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cytokines

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small proteins (<30 kDA) that signal between cells

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autocrine

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cytokine acts back on the producing cell (ex. IL-2)

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paracrine

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cytokine acts on neighboring cell or cells (ex. IFN-gamma)

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endocrine

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cytokine acts on distant cells (IL-5)

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cytokine signal transduction

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1. activation of JAK family tyrosine kinases, phosphorylation of receptor (tyrosine phosphorylation of STAT by JAK kinase)
2. Dimerization of STAT
3. Specific gene transcription

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function of IFN-gamma

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1. activates macrophages
2. induces B-cells to class switch to IgG2
3. Helps CTL differentiation

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function of IL-4, IL-5, and IL-13

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1. induces B-cells to class switch to IgE
2. induces eosinophil differentiation and activation

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function of IL-17 and IL-21

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1. important at mucosal surfaces
2. induces neutrophil recruitment
3. specific role in B-cell class switching unclear

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intracellular bacteria and viruses mediate the following immune responses:

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1. cell-mediated immunity
2. activated macrophages
3. opsonization
4. CTL production

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extracellular bacteria and fungi mediate the following immune responses:

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1. tissue inflammation
2. recruitment of neutrophils
3. activates macrophages
4. opsonization

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worms and large parasites mediate the following immune responses:

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1. humoral immunity
2. IgE production
3. degranulation of mast cells
4. eosinophils

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which B-cells isotypes are good at neutralization?

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IgG1, IgG2, IgG3, IgG4, IgA

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which B-cell isotypes are good at opsonization?

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IgG1, IgG3

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which B-cell isotypes are good at sensitization for killing by NK cells

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IgG1, IgG3

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which B-cell isotypes are good at sensitization of mast cells

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IgE

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which B-cell isotypes are good at activating complement?

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IgM, IgG1, IgG3