Cytokines Flashcards
IL-1
From monocytes, macrophages, etc
Fever,acute phase response, induces IL-2R expression and I’ll-2 synthesis in T cells
IL-1
Monocytes, macrophages, many others
Pyrogen (fever), acute phase response; induces IL-2R expression and IL-2 synthesis in T cells; enhances adhesion molecule expression on leukocytes and endothelial cells
IL-2
TH1, others
T cell growth factor; activates T cells and NK cells
IL-3
T cells, others
Stimulates hematopoiesis
IL-4
TH2, mast cells, others
Promotes TH2 development; inhibits TH1 development; promotes IgE or IgG4 synthesis by B cells
IL-5
TH2, mast cells
Eosinophil development; class switching to IgA in B cells
IL-6
macrophages, others
Stimulates acute phase protein synthesis; low-level pyrogen, stimulates differentiation of B cells to plasma cells
IL-7
Bone marrow and thymic stromal cells, some T cells
Growth factor for pre-T and pre-B cells
IL-8
Macrophages, fibroblasts, endothelials, others
Chemokine that attracts neutrophils and naive T cells
IL-10
Treg
Inhibits T cells, macrophages, others; protects against autoimmunity
IL-12
Activated macrophages, dendritic cells, B cells
Activates TH1 and NK cells
IL-13
TH2 cells
B cell growth factor; class switch to IgE or IgG4
IL-17
TH17 cells
Pro-inflammatory, promotes neutrophil migration and differentiation, defensin production
IL-22
TH17 cells, others
Promotes defensin production by stromal and epithelial cells
IFN-a AND IFN-b (Type 1)
Most cell types
Induced by intracellular pathogens; anti-viral; induces class I MHC expression
IFN-g
TH1 cells, NK cells
Selects TH1 subset; inhibits TH2 subset; activates macrophages, NK and Tc cells; enhances respiratory burst in macrophages; causes class switch to IgG3; promotes class I and II MHC expression
TNF-a
Macrophages, others
Inflammation; induces shock and cachexia; enhances adhesion molecule expression; enhances phagocytosis and respiratory burst in macrophages; induces fever, acute phase protein release
TNF-b
TH1, Tc cells
Kills infected cells, tumors by inducing apoptosis
GM-CSF
M-CSF
G-CSF
T cells, macrophages, mast cells, natural killer cells, endothelial cells and fibroblasts
Promotes growth of granulocytes and/or monocytes, as indicated by name
Some potent superantigens include:
- TSST-1: toxic shock syndrome toxin 1 made by Staphylococcus aureus
- Enterotoxins from S. aureus that cause food poisoning
- Pyrogenic toxins produced by Streptococcus pyogenes
TNFA and IL-1 are particularly damaging,
SHOCK
•Low blood pressure
- Fever
- DIC (disseminated intravascular coagulation, i.e. platelet deposition)
- Cardiovascular shock
- Cachexia (wasting of muscle and fat)
Superantigens
microbial toxins that stimulate as many as one in five T cells. They do not need to be processed by an APC in order to stimulate T cells. They bind simultaneously to Class II MHC molecules on the APC and the β chain of the TCR. They induce release of all the T cell and macrophage cytokines discussed so far.
CD8+Tc Cell Functions
The major functions of CD8+Tc cells are the killing of infected host cells, tumor cells, and foreign tissue grafts.
•They kill their target cells by secreting:
- Perforin, which punches holes in the target cell membrane
- Granzymes that enter through the holes to induce caspase-mediated apoptosis
- Granulysin, which mediates killing of Listeria, Mycobacterium spp., and other intracellular bacteria
•Tc cells express the surface proteinFas ligand(FasL)
- FasL binds to “death receptor” Fas (CD95) on the infected cell
- Engagement of Fas by FasL activates caspases that induce apoptosis in the target cell
•Apoptotic cells are rapidly phagocytosed, preventing spread of virions without inflammation
CD8+Tc Cell Functions
The major functions of CD8+Tc cells are the killing of infected host cells, tumor cells, and foreign tissue grafts.
•They kill their target cells by secreting:
- Perforin, which punches holes in the target cell membrane
- Granzymes that enter through the holes to induce caspase-mediated apoptosis
- Granulysin, which mediates killing of Listeria, Mycobacterium spp., and other intracellular bacteria
•Tc cells express the surface proteinFas ligand(FasL)
- FasL binds to “death receptor” Fas (CD95) on the infected cell
- Engagement of Fas by FasL activates caspases that induce apoptosis in the target cell
•Apoptotic cells are rapidly phagocytosed, preventing spread of virions without inflammation
T Cell Activation Requires 2 Signals
Signal 1: interaction between the TCR and the peptide/MHC complex on the APC. CD4 or CD8 acts as a co-receptor molecule
Signal 2 is provided by multiple co-stimulatory interactions between cell surface molecules on the T cell and the APC. (CD40L, CD28, CTLA-4)
T cell molecule:
CD40L
CD28
CTLA-4
APC and function:
CD 40- enhance CD28-B7 interaction, class switching in B cells
B7- secretion of IL2 and expression of IL2 receptor; required for T cell act and prol
B7- inactivates Tcell, wanes immune response
Major function of CD4 T cell
cytokine production
TH1 Cells
promote cell mediated immunity, and delayed type hypersensitivity
good against intracellular pathogens: activate Tc, NK cells, and macrophages
IFN-g above plus class switch to IgG3 (opsonize antigens and activates compliment) up regulates MHC prevents TH2 maturation
produce IL2
promoted by IL12/IFNg
TH2 Cells
promote anti-worm immunity and immediate hypersensitivity reactions (allergies)
-They secrete:
▪IL-4 and IL-13: induce class-switch to IgE and IgG4 synthesis by B cells
▪IL-5: induces class-switch to IgA, activates eosinophils
- IL-4 produced by mast cells and mature TH2 cells promotes maturation of developing TH2 cells and prevents maturation of TH1 cells
- IL-4 induces the transcription factor GATA-3, which directs TH2 development
TH17 cells
cells promote immunity to extracellular bacteria and fungi
- May contribute to autoimmune diseases, e.g., multiple sclerosis, psoriasis, and rheumatoid arthritis
- They secrete:
▪IL-17: promotes neutrophil migration and differentiation
▪IL-22: induces cells in the skin and digestive system to synthesize defensins (antibacterial peptides)
-The cytokines involved in TH17 development are controversial but may include transforming growth factor beta (TGFb), IL-6, IL-21, and IL-23.oTH17 development is regulated by the RORgt transcription factor
Treg Cells
cells suppress the differentiation and functions of TH1, TH2, TH17, monocytes, macrophages, and other cell types
Protect the body from autoimmune reactions
They secrete:
▪IL-10: generally immunosuppressive for T cells and macrophages
▪TGFβ (transforming growth factor beta): inhibits T cell and macrophage function, promotes wound healing
Treg development is promoted by TGFb
Treg development is regulated by the Foxp3 transcription factor
Mutations in Foxp3 lead to IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome). IPEX manifests with autoimmune enteropathy, psoriasiform or eczematous dermatitis, nail dystrophy, and autoimmune skin conditions such as alopecia universalis and bullous pemphigoid. Boys are affected, while girls are carriers and might suffer mild disease.
Cytokine Receptor-Mediated Signal Transduction
The binding of a colony stimulating factor, interferon, or interleukin to its receptor results in signal transduction in a step-wise fashion: (6)
The binding of a colony stimulating factor, interferon, or interleukin to its receptor results in signal transduction in a step-wise fashion:
- Receptor-ligand binding causes receptor polypeptides to dimerize or polymerize at the target cell surface
- The juxtaposed cytoplasmic tails of the receptor polypeptides activate JAK tyrosine kinases
- The JAK kinases phosphorylate the cytoplasmic domains of the receptorand the STATtranscription factors (signal transducers and activators of transcription) in the cytoplasm
- Once phosphorylated, STATs dimerize and then translocate to the cell nucleus, where they bind to enhancer regions of certain genes
- The genes are transcribed into RNA and translated into proteins
- Inhibitors of the JAK-STAT pathways comprise therapies for several organ cancers (breast, prostate, pancreas), blood system cancers (polycythemia vera, multiple myeloma, essential thrombocythemia), and autoimmune diseases (psoriasis, rheumatoid arthritis, ulcerative colitis, dry eye syndromes)
Proteins on the T cell surface
TCR
CD3
CD4
CD8
Proteins on the APC
The degree of similarity between the MHC molecules of donors and recipients will determine whether a graft is accepted or rejected. The function of MHC molecules is to present processed antigens to T cells. In humans, the MHC is called the HLA (human leukocyte antigens).
Class I HLA
Class II HLA
T cell receptor for antigen (TCR)
- The two polypeptide chains of the TCR have variable (V) and constant(C) region exons whose rearrangement is mediated by the RAG-1 and RAG-2 enzymes of the VDJ recombinase. However, unlike antibodies, TCRs are not secreted and do not undergo affinity maturation
- 95% of all T cells express a and b chains. ab-TCR molecules recognize protein antigens presented by MHC molecules
- 5% of T cells express the gd-TCR and recognize lipids, glycolipids, and phospholipids presented by the CD1 molecule. gd-T cells protect mucosal epithelial cells in skin, gut, lung, etc. from bacteria. Most are cytotoxic cells
CD3
always found associated with the TCR. Its 6 protein chains (g-d, dd, ??) transmit a signal to the T cell nucleus when TCR binds to antigen
CD4
a co-receptor found on all TH cells and Treg cells. It is a single-chain transmembrane glycoprotein that binds to class II MHC molecules on antigen-presenting cells
CD8
a co-receptor found on all Tc cells. It is a transmembrane glycoprotein comprising an a chain and a b chain. It binds to class I MHC molecules on antigen-presenting cells, including infected, nucleated cells.
Class I HLA molecules
re found on all nucleated cells and platelets, but not on red blood cells. They present antigen to Tc cells expressing the CD8 molecule. Class I HLA molecules are composed of an a chain encoded by the HLA-A, HLA-B, and HLA-C genes on chromosome 6;and the b2-microglobulin chain encoded on chromosome 15.
Class II HLA molecules
are constituitively expressed by the professional APCs, which include dendritic cells, macrophages, monocytes, and B lymphocytes. Expression of class II HLA can be induced on other cell types by interferon gamma (IFNg). Class II molecules present antigen to TH and Treg cells that express CD4. They are composed of an a chain and a b chain encoded by the HLA-D region genes (HLA-DP, HLA-DQ, HLA-DR) on chromosome 6.
Describe the inheritance of HLA genes.
HLA genes are inherited as a single unit on each copy of chromosome 6 inherited from a child’s parents. Therefore, 50% of a child’s HLA genes will be identical to his mother’s HLA genes, and 50% will be identical to his father’s HLA genes.
Genes that are inherited together as a unit from each parent are called…
haplotypes.
Humans have two HLA haplotypes, one from the mother and one from the father. There is a 25% likelihood that a child will be a perfect HLA match to one of his siblings from shared parents.
Class I HLA molecules present ____ antigens,
endogenous
- Viral antigens are processed by proteasomes(enzyme complexes)
- Peptide fragments are transported by TAP molecules (transporter of antigenic peptides) to the ER (endoplasmic reticulum)
- Peptide fragment is loaded into the Class I molecule, and then transported within a Golgi body to the surface of the host cell
- Tc cells with TCRs specific for the viral peptides are induced to kill the host cell
Class II HLA molecules present ____ antigens
exogenous
Phagosome or endosome fuses to an acidic vesicle→change in pH activates proteolytic enzymes(cathepsins)that degrade the engulfed microbe
- Meanwhile, Class II molecules are being synthesized in the ER of the phagocytic cell, along with an invariant chain (Iior CD74)
- The invariant chain blocks the Class II peptide binding groove from becoming loaded with endogenous peptides
- When a Golgi body containing the Class II molecule fuses to the vesicle containing the degraded microbe, the invariant chain is destroyed, and the microbial peptides are loaded into the groove of the Class II molecules
- The Class II/microbial peptide complex is then transported to the surface of the host cell for presentation to TH cells with TCRs specific for the microbial antigens
- TH cells are induced to secrete cytokines
Antigen cross-presentation
Dendritic cells have a unique method of presenting exogenous antigens to CD8+Tc cells in conjunction with Class I MHC molecules
- The dendritic cell takes up the exogenous antigen by phagocytosis or pinocytosis
- The antigen is transferred from the acidic vesicle to the cell cytoplasm
- The antigen is degraded by the proteasome, and the resultant peptides are trafficked to the endoplasmic reticulum by TAP molecules
- Antigenic peptides occupy the grooves of MHC Class I molecules and are transported to the cell surface for presentation
