2. Effector Mechanisms of T Cell Mediated Immunity Flashcards
Ag-activated T cells repond by producing IL2 and express IL2R receptors leading to cell proliferaiton, resulting in expansion of the clone of T cells that are specific for the Ag. Some differentiation in effector cells which serve various function in T cell mediated immunity and others differentiate into ________?
Memory cells which survive for long periods
Each subset of T helper cells (CD4) produce particular cyotkines, this is called differentiation/commitment. Th0 cell activation generates Th1, Th2, Th17, and Tfh, which do what?
Th1 cells: activate cell mediated immune reponse
Th2 cells: activate Ab-mediated immune reponse
Th17 cells: involved in inflammation and anti-bacterial response
Tfh cells: follicular helper T cells remain in LN and help B cells
Treg is induced by IL2/TGFB, produces IL10 and functions in?
regulate inflammation response
suppresses tumor immunity
promotes immune tolerance
maintains lymphocytes homeostasis
Th1 is induced by IL12/IFNG, produces IFNG,TNF and functions in?
Macrophage activation and inflammation
Th2 is induced by IL4, produces IL4, IL5, IL13, and functions in?
allergy, asthma, wormsss
Th 17 is induced by IL6/TGFB, produces IL-17A, IL-17F, and IL22 and functions in?
Inflammation
Tfh is induced by IL6/IL21, produces IL4,IL21 and functions in?
germinal center help
PRR signaling causes activation and maturation of Ag-presenting cells (APCs), which presents to Th0 (naive cells). secreted IL12 develops Th1 cells, IL4 develops Th2 cells, and TGF and IL6 develops ________?
Th17 cells
Th1, 2 and 17 are all CD4+ helper cells. Th1 assists in mø activation and IgG production (intracellular microbes), and assists in autoimmune diseases
Th2 assists in mast cells, eosinophil activation, IgE prod, (helminthic parasites) and role in disease is allergic disease
Th17 immune reaction is neutrophilic, monocytic inflammation, (extracellular bacteria/fungi) and role in disease is?
Autoimmune inflammatory diseases
Cytokines are produce transiently in response to antigen. Usually acts on same cell that produces the cyotkine (autocrine) or nearby (paracrine). They have pleiotropism (multiple biological actions) and redundancy which is?
multiple cytokines may share the same or similar biological activities
IL2 is produced by activated T cells, is the FIRST. transforming growth factor B (TGF-B) functions mainly as?
An inhibitor or damper of immune reponses but stimulates differentiation of T reg cells
DCs/Mø when bound by a microbe, produce IL12 which activates transcription factors STAT4 and T bet. NK cells produce IFNy which activates STAT1, which together do what?
Stimulate the differentiation of naive CD4+ T cells into Th1 subset
Th1 cells amplify this response by producing IFNy which inhibits the development of?
Th2 and Th17
The release of extra IFN-y by Th1 cells assists with macropahge activation and what?
complement binding and opsonizing IgG antibodies
Once activation of effector cell is complete, meaning CD28 and B7 are bound along with the Ag, CD40 is constituitively expressed on the Mø. CD40L (located on the X-chromosome) is then induced on the T cell and ?
Binds to CD40 on the Mø as well as IFNy is released to activate the Mø to kill the phagocytosed bacteria
There are 3 main responses of an activated Mø:
1. production of ROS,NO and lysosomal enzymes
2. secrete TNF, IL1, IL12
3. Increase expression B7 and MHC
Why do they do this?
- To kill microbes
- to recruit leukocyte (inflammation) (TNF/IL1)
- To increase T cell activation/amplification
For developing Th2 cells: activated mast cells and eosinophils produce IL4, which activates GATA-3 and STAT 6 which stimulates Th2 subset of CD4+ T cells. IL4 produce by the Th2 cells amplifies this response and inhibits…..?
The development of Th1 and Th17 cells
Released IL4 produces IgE to help with mast cell degranulation
IL4/IL13 help with intestinal mucus secretion and peristalsis and also activates alternative Mø (tissue repair)
IL5 will do what?
Activate eosinophils against helminthes
Classically activated macrophages (M1) are activated by Th1 cells and result in ROS/NO for microbial phagocytosis and IL1 IL12 IL23 and chemokines to assist in inflammation
Alternatively activated macrophages (M2)….?
are activated by Th2 cells, which cause the Mø to release IL 10 and TGF-B for anti-inflammatory effects, wound repair, fibrosis and to inhibit inflammation
In balancing Th1 and Th2 in the outcome of infections, Th1 tells the macrophage to kill the microbes inside and Th2..?
Inhibits microbicidal activity of macrophages causing cell-mediated immunity and mø activation
When infected with Leishmania major, mice with Th1 recovered, and mice with Th2 has a disseminated infection. When infected with myobacterium leprae, mice with Th1 had tuberculoid leprosy and mice with defective Th1 or dominant Th2 got…?
Lepromatous leprosy (high bacterial count) this signifies that you need a balance between Th1 and Th2 to overcome and infection, not just one or the other
Bacteria and Fungi activate DCs and T cells to release IL1, IL6, and TGFB which activates TFs RORyt and STAT3. RORyt and STAT3 stimulates IL21 which?
Amplifies the generation of Th17 cell in an autocrine regulatory manner
TGFB may promote Th17 by supressing Th1 and Th2 (which inhibit Th17). IL 23 made by M1 macrophages are important in activation of Th17. Th17 cells produce IL 17 which does?
Protects from extracellular pathogens and is involved in tissue inflammation and autoimmunity
When there is an increased level of IL17 and IL22 due to Th 17 cells, chemokines, TNF, IL1 and IL6 are released and cause inflammation and neutrophil response. When IL17/22 levels are constitutive what is made?
Antimicrobial peptides are formed and there is increased barrier function
CD markers are used for fluorescent microscopy and flow cytometry. T lymphocytes marker is CD3 in 100% of T cells in blood and are thymus derived. What about for Helper T cells (Th) and Cyotoxic T lymphocytes (CTLs)?
Th: CD4 marker, 66% of T cells in the blood, Are class II MHC restricted CTL: CD8 marker, 33% of T cells in the blood, Class I MHC restricted
After Ag recognition and costimulation between CD28 and CD80, Naive CD8+ T cells proliferate and differentiation into effector CTLs. They secrete IFN-y to activate mø, use granzymes and peforin to kill other cells and like Th1, it involves which transcriptional factor?
T bet
Cells infected with intracellular microbes (viruses) are ingested by DCs, which are then processed and presented with Class II MHC and class I MHC… How?
Ag cross-presentation, some viral Ags are released from phagosome in the cytoplasm of DCs and presented with class I MHC. Same APC can also display Ags within Class II MHC for CD4 helper cells
What is significant of the generation of effector CD4 T cells and CD8 T cells?
CD4 T helper cells are produced before CD8 T cells by a day or two, because CD8 depends on CD4 t cell mediated DC licensing via CD40-CD40L
CD4 are made before CD8 because the DCs need to be educated or licensed first and this takes time. What is the main contributor to licensing?
CD40/CD40L
Licensing of the APC occurs when the CD4 t cell delivers activating signals through CD40/CD40L and cyotkines such as IFNy to the DC after it recognizes the Ag presented by MHC II. The activated CD4 Th cell then does what?
Increases expression of CD40L which may bind to CD40 on Ag-loaded DCs
the CD40-CD40L and IFN-y interaction upregulates expression of CD80/CD86 on the APC and stimulates Ag cross-presentation which makes them more efficient at?
inducing differentiation of CD8 T cells
One way a CD8 t cell can differentiation into CTLs is by recognizing an Ag and costimulators on professional APCs which releases what and leads to?
Releasing IL12 and causing differentiation of CTLs
CD4+ helper T cells produce which cytokines that stimulate CTL differentiation?
Produce IL2 which causes a potentiated response
CD4 helper cells can also enhance the ability of APCs (with CD40/CD40L?) to stimulate CTL differentiation… such as?
CD4 Th releases IFNy which enhances the APC to release more IL12 which potentiates a response to become a CTL
CTL mediated cytotoxicity involves specific TCR dependent recognition and induction of apoptosis in target cells. Recognizes MHC , bringing the CTL and Target cell close which results in?
the formation of the immunologice synapse
The immunologic synapse ensures normal bystander cells are not injured by the perforin and granzymes secreted into the synapse (which perform the killing) by….?
Not allowing them to diffuse to nearby cells
There are two major ways of kill infected cells by CTLs, they are?
Complex of perforin and granzymes mediated killing
FasL/Fas cell mediated killling
Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes delivered to the cytoplasm of the target cells by a perforin dependent mechanism and induce apoptosis. How does the FasL/Fas complex work?
FasL is expressed on activated CTLs, binds to Fas on target cells and causes target cell apoptosis
Granzyme mediated apoptosis: there are granzymes A B and C which are serine proteases. Granzyme B is the only one shown to be require for CTL cytotoxicity. Perforin is a membrane-perturbing molecule that is homologous to?
C9 complement protein!
Perforin insertion into the target cell membrane elicits a compensatory membrane repiar process in the target cell that leads in internalization of both perforin and granzumes into endosome. Once inside granzyme B….
activates caspase-3 which activates CAD by cleaving ICAD and allow DNA degredation = apoptosis in the cell
In Fas-FasL mediated apoptosis, bind FasL to Fas recruits procaspase-8 through the FADD adaptor and converts it into the active enzyme: caspase 8. In type I cells such as thymocytes, caspase 8 directly cleaves?
caspase 3
In type II cells such as virus infected hepatocytes, caspase 8 cleaves Bid and the truncated Bid stimulates the release of what from the mitochondria?
Cytochrome c
Cytochrom C with apaf-1 (apoptotic peptidase activating factor 1) and ATP activates caspase-9 which also activates?
Caspase 3
Caspase 3 activates CAD (caspase activated DNase) via degradation of ICAD (inhibitor of CAD). Activated CAD causes?
DNA DEGREDATION = APOPTOSIS
CD8 cooperate with CD4 T cells in defense against intracellular microbes such as L. monocytogens, which are phagocytized by Mø and may survive in phagosomes and escape into the cytoplasm. CD4 t cells respond to class IIMHC Ag derived from bacteria and produce?
IFN-y and IL2…. CD8 respond to MHCI Ags derived from viruses and release IFNa/b
overview of CD8 CTLs in viral infections:
- Virus infects, degraded into peptides, presented by MHC1 to CD8T cells
- DCs pick up Virus particles/reminants of virus
- Viral peptides presented MHC1 vias cross-presentation
- CD4 recognize MHCII, they ACTIVATE DCs by CD40 binds CD40L
- Activated DCs increase expression of CD80/86 and bind to CD28 on naive CD8
- ?
- ?
- CD28/TCR signaling result in activation and dIfferentiation of activated CD8 T cell
- Activated to effector CD8 T cell, binds viral Ag and either FasL/Fas or perforin/granzyme mediated target cell death and production of cyotkines TNFA and IFNy
Mycobacteria evades cell mediated immunity by?
inhibition of phagolysosome fusion (phagosome with bacteria does not fuse with lysosome with enzymes)
Herpes simplex virus (HSV) evades cell mediated immunity by?
inhibition of antigen presentation: HSV peptide inteferes with TAP transporter (not allowing peptide/Ag into ER to bind MHCI)
Cytomegalovirus (CMV) evades cell mediated immunity by?
inhibition of antigen presentation: inhibition of proteasomal activity AND inhibition of the removal of class I MHC molecules from ER (proteasome breaks down protein so its presentable and removing molecule from ER is need to present to CD8)
Epstein-Barr Virus (EBV) evades cell mediated immunity how in CD8 presenation?
inhibition of antigen presentation: inhibition of proteasomal activity, which inhibits antigens to be attach to MHCI to be presented
Epstein-Barr Virus (EBV) evades cell mediated immunity how in an infected B cell?
Production of IL10, inhibition of macrophage and dendritic cell activation (IL10 antiinflammatory= will not activate mø)
Pox virus evades cell mediated immunity by?
inhibition of effector cell activation: production of soluble cytokine receptors (IL1R/IFNyR soluble, no cytokine receptor for cytokines to bind to to active macrophage)
