Immuno-Cytokines-T cell effectors
Terms
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- Cytokines important points
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-Important mediators of cell-cell communication
-generally, act locally
-paracrine and autocrine
-dependent on receptor expression - Cytokines definition
- proteins secreted by cells of host defense that regulate the immune response
- lymphokines
- cytokines produced by lymphocytes
- monokines
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cytokines produced by monocytes/macrophages
e.g., IL-1, TNFa, IL-6 - interleukins
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cytokines produced by WBCs and act on WBCs
e.g.,IL-1 through IL-25 (more?) - chemokines
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low molecular weight molecules important in the inflammatory response; chemotaxis
e.g., IL-8, RANTES, etc -
A given cytokine can be
pleiotrophic -- give definition - different biological effects on different target cells
- Cytokines can be redundant -meaning
- multiple cytokines having a similar activity
- Cytokines can be synergistic -meaning
- cytokines that work together
- Cytokines can be antagonistic-meaning
- cytokines that work against each other
- Th cells can be divided into two major subsets. Name them, the type of immunity they produce, and the cytokines associated with them
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Th1 – CMI
IL-2, IFNg, TNFb
Th2 – Humoral
IL-4, IL-5, IL-10 - What is the importance of Th subsets in leprosy
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Th1 response with cell mediated immunity results in tuberculoid leporacy - you have granuloma, nervous and skin tissue damage but the patient usually survives.
Th2 ab response results in disseminated disease and a fatal outcome - mRNA levels for Th cell cytokines in patient with tuberculoid lepracy show high levels of mRNA for which cytokines
- TNFbeta, IFNgamma, IL2
- mRNA levels for Th cell cytokines in patient with full blown disseminated leprocy show high levels of mRNA for which cytokines
- IL-4,IL-5,IL-10
- Importance of Th subsets in HIV/AIDS
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-CMI more effective
-progression to AIDS has been associated with Th1 to Th2 shift -
Activity of cytokines
Cytokines must bind to a specific _________ after binding receptor, a _________ occurs within cell to exert a biological activity (changes in gene expression) - cytokine receptor/signaling cascade
- Cytokines have a short in vivo half life therefore, they ________
- act locally
- Cytokine receptors often have at least TWO chains. What are they?
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1)cytokine specific unit
2)signal transducing unit - cytokine receptors have a common _______ cytokine specific subunit
- gamma
- signalling chain is often the same within a
- cytokine receptor family
- Often get _____ binding when have two (or three)signalling chains
- higher affinity
- After cell activation, get ____________
- increased cytokine receptor expression
- X-linked SCID results from
- defect in g chain gene
- What are three ways microbe evasion of host response relating to cytokines
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They act as cytokine antagonists --molecules that bind cytokine receptors but don’t send signal
they bind to cytokine--
prevent cytokine binding to receptor
They mimic cytokine receptor - Cytokine related diseases
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Bacterial septic shock-LPS causes high levels of cytokine release
Toxic shock diseases-
superantigens
Lymphoid and myeloid cancers
e.g., Adult T cell leukemia – overproduction of IL-2 - Therapeutic uses of cytokines
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Graft survival
Lymphokine activated killer cells (LAK)
Tumor infiltrating lymphocytes (TILs)
Direct administration of cytokines - What do Th cytokines do
- cells produce cytokines to regulate the immune response
- What do Tdth (delayed type hypersensitive) do
- cells produce cytokines to stimulate an inflammatory response
- What do Tc (cytotoxic) cytokines do
- cells produce cytokines that kill target cells
- What do Tc (supressor) cytokines do
- cells produce cytokines to turn off the immune response
- CTLs
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important in eliminating
-altered self cells
-virally infected cells
-tumor cells
foreign graft tissue - CTL - Cytotoxic response
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Phase 1: generation of CTLs
-Naïve CTLs must be activated
-TCR : Ag/MHC interaction
-CD28 : B7 costimulation
-IL-2 stimulation (from Th cells)
Phase 2: destruction of target cells
-directional delivery of cytotoxic proteins - Describe CTL action on target cell
- after CT; recognition of target cell: the GOLGI “moves†near cell membrane and releases cytotoxic mediators at the Tc:target cell interface
- CTL cytotoxic proteins
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PERFORIN
GRANZYMES
FASL - PERFORIN
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pore forming
similar to C’ pore formation - GRANZYME
- enter target cell through pores HAS enzymes that produce DNases within target cell resulting in cell apoptosis
- FASL on CTL and FAS on target cell interaction
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-Cascade of events yielding apoptosis
-TNFa binds to Fas (can kill tumor cells directly) - NK cell mediated cytotoxicity
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-similar to CTL but no Ag specific recognition
-produce perforin and granzymes
-don’t need prior activation (constitutive expression of these molecules) - ADCC (antibody-dependent cell-mediated cytotoxicity)
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the Ab is the signal to attract non-specific cells to the target cell.
Ab are bound to Ag on the target cell and Fc receptor on the NK cell, neutorphil, eosinophil, or macrophage.
The release of granules from the NK cell, the neutrophil, the eosinophil , or the macrophage results in dealth of the target cell.