naïve T cells require two activation stimuli. name them
1) binding of TCR to specific peptide antigen:MHC complex
2) co-stimulatory signal supplied by interaction between CD28 (on the T cell) with B7 molecules (expressed by antigen-presenting cells)
What is the only cell that expresses B7 molecules?
When is B7 expression upregulated in APCs?
in response to potential infection
T/F armed effector T cells require only a single activation stimulus
What is the only activation stimulus needed by armed effector T cells? what is the result?
Stimuli => binding of TCR to specific peptide antigen:MHC complex
- when armed effector T cells recognize their specific antigen, they are quickly activated to perform their effector function
naïve T cells and effector T cells express a different array of what?
What reflects and defines the roles of adhesion molecules in immune response?
expression by naive T cells and by effector T cells
naïve T cells must enter the secondary lymphoid tissues via process? Describe this process
mediated by surface adhesion molecules (L-selectin) to have a chance to become stimulated by an antigen presenting cell
What keeps naive T cells from entering into inflammatory sites?
they do not express the adhesion molecules (VLA-4) required for entry into inflammatory sites
Why does it not make sense for naive T cells to be in inflammatory sites?
they have no effector functions and no role in the environment
What allows armed effector T cells to perform their effector functions?
expression of a different array of adhesion molecules
Why can effector CD8 T cells not enter secondary lymphoid tissue?
effector CD8+ T cells (CTLs) down-regulate expression of L-selectin
What allows CTLs to bind to vascular endothelium at sites of inflammation?
upregulate expression of VLA-4
Why is it important for CD8 T cells not to enter secondary lymphoid tissues?
1) they have no role there
2) if they entered secondary lymphoid tissues, they could attack antigen-presenting cells that present their specific peptide antigen
What allows CD8 T cells to enter inflammatory sites so they can "target" cells?
down-regulation expression of L-selectin
upregulation expression of VLA-4
How does effector CD8 T cells initiate interactions between the effector T cells with their potential “target” cells?
upregulate expression of cell adhesion molecules (LFA-1 and CD2)
Which is not an effector molecule produced by helper T cells?
T/F Both CD4 and CD8 effectors can initiate apoptotic deal of host cells
What promotes differentiation of CD4 Tcell into Th1 type cell?
high Ag concentration; IL-12 + IFN-y
the effector molecules produced by T cells fall into 2 broad classifications. Describe each of them
1. cytotoxins- perforin, granzymes, Fas ligand
- cytotoxins are the principal effector molecules of CTLs
2. cytokines - IFN-y, GM-CSF, TNF-a, LT, IL-3, IL-4, IL-5, IL-10, IL-13, TGF-B;
- cytokines are the primary effector molecules for CD4 T cells;
What defines the Th1 and Th2 cells?
defined by the cytokine profiles they produce
Th1 cells produce what type of cytokines?
cytokines that upregulate macrophage functions and generally promote cell-mediated immunity
Th2 cells produce what type of cytokines?
generally promote humoral immune responses
Define cytokine and their effects
small soluble proteins that can act on the secreting cell, or on a different cell
the effects many cytokines have on cells have been determined
What is the primary cytokine produced by CD8 cells? Name its function/role
anti-viral properties and inhibits TH2 cell development
TH1 CD4 cells produce what type of cytokines? and name their role/function
IL-2 and IFN-y
lymphotoxin and other inflammatory cytokines
Th2 CD4 cells produce what cytokines?
IL-4, IL-5 and IL-10
CD4 cells activated in presence of IL-12 and IFN-γ will become
CD4 cells activated in presence of IL-4 and IL-6 will become
What does a Th1 use its cytokines for? name them and overall function
- macrophage activation
- B cell activation
- production of opsonizing Abs such as IgG1
What does a Th2 use its cytokines for? name them and overall function
- General activation of B cells to make Abs
Describe the differentiation from Th0 cells to Threg cells
Describe the differentiation to Th1 cells
Describe the diffentiation to Th2 cells
antigen presented to TH0 cell influences differentiation pathway. What does low affinity or concentration go toward?
presentation of low affinity or low concentration of Ag >>>> TH2
antigen presented to TH0 cell influences differentiation pathway. What does high affinity or concentration go toward?
presentation of high affinity or high concentration of Ag >>>> TH1
What is the role of CTLs wrt infection?
destroy infected cells, thereby limiting the infection
How do CTLs know how to target the correct cell?
proteins from these intracellular parasites (viruses and intracellular bacteria) are processed and presented on MHC class I molecules to CD8 T cells
When can an effector CD8 T cell initiate killing of the infected cell?
effector CD8 T cell (CTL) recognizes its cognate peptide antigen:MHC complex presented on any cell
the 1st step of specific antigen recognition by a CTL (or a CD4 T cell for that matter) is what?
interaction of the T cell with the target cell (or APC for CD4 T-helper cells) mediated by cell surface adhesion molecules
once in close proximity, interaction between TCR and MHC:peptide complexes can occur
T/F TCR must recognize the specific peptide or will disengage
What does a CTL contain and express that help with the mechanism of cell killing by CTLs?
CTLs contain granules that contain perforin and granzymes;
CTLs also express Fas ligand
once a CTL recognizes its specific peptide antigen:MHC complex, what occurs?
What are molecules polymerize to form a pore in the membrane of the target cell?
What a detergent like protein that associates with cellular membranes?
What are serine proteases that activate programmed cell death (apoptosis) of the target cell?
How do granzymes gain access to the interior of the cell?
repairative endocytosis model via a cation-independent mannose-6-P receptor (CI-MPR)
What is the action on the target cells via perforin?
aids in delivering contents of granules into cytoplasm of target cell
What is the action on the target cells via granzymes?
Serine proteases, which activate apoptosis once in the cytoplasm of target cell
What is the action on the target cells via granulysin?
has antimicrobial actions and can induce apoptosis
What is the Fas ligand?
engages with Fas on the target cell, helping to induce apoptosis
What increases the chances that an infected cell will be recognized by an antigen-specific effector CTL?
CTLs also produce cytokines (IFN- , TNF- , and TNF- ) that stimulate cells to upregulate expression of proteins involved in antigen presentation to MHC I
What is a Th1 cytokine and CTL effector molecule?
Describe the process of apoptosis mediated by CD8 cells
Fas ligand binds to Fas
adaptor proteins recruit and activate caspase 8 which cleaves caspase 3
Activated caspase 3 cleaves I-CAD which inhibits CAD (caspase-activatible DNase) that is released into nucleus and cleaves DNA
CTLs, as well as T helper cells, become polarized when their TCR is bound to MHC:peptide complexes- why is this important?
this polarization focuses the effector molecules released by the T cell onto its specific target cell
How do the CTLs and T helper cells become polarized?
reorientation of the cytoskeleton of the T cell polarizes the T cell so that effector molecules are focused on the target cell
What is the most important function of CTLs wrt its mechanism of killing cells?
ability of T cells to focus their effector molecules onto their specific target cells is vital to their function
effector function only on cells that bear the cognate peptide antigen:MHC complex that binds to the TCR of the effector T cell
What is the fate of cells targeted by CTLs? What other cell is this similar to?
programmed cell death is the ultimate fate of cells killed by antigen-specific effector CTLs
What are the 2 stimuli that can cause apoptosis?
mediated by granzymes, which are serine proteases that initiate the programmed cell death pathway
initiated by interaction of Fas on a target cell with Fas ligand (FasL) expressed on effector cells
regardless of the initiation signal, all apoptosis initiators lead to what?
activation of a series of cysteine proteases known as caspases
the inactive form of CAD (I-CAD) is present in all cells of the body. What inhibits I-CAD to allow for DNA cleaving?
cascade of caspase activity
activate macrophages to kill bacteria and other pathogens is an effector function of what cells?
Th1 CD4 cells
both signals required to activate macrophages can be delivered by Th1 Cells. What are they?
CD40 ligand interacts with CD40 (on macrophage)
activation of a macrophage leads to a number of biochemical responses by the macrophage (5)
•• upregulation of phagosome-to-lysosome fusion which leads to destruction of ingested pathogen
•• production of NO and oxygen radicals, both of which have potent anti-bacterial activity
•• production of antibacterial peptides and proteases that are released and can attack extracellular parasites
•• upregulation of surface molecules; MHC class II molecules, B7 (costimulator for presenting antigen to T cells), CD40
•• production of IL-12 which stimulates differentiation of TH0 cells into TH1 T cells
What cells coordinate the host response to intracellular pathogens?
How do T cells regulate the activities of
macrophages during a cellular immune response?
T cells produce a variety of cytokines and cell surface markers
in response to specific antigen recognition by an effector TH1 cell, the TH1 cell:
•• produces IFN- and CD40 ligand which are the signals for activation of macrophages; makes macrophages more bacteriocidal
•• produces TNF- apoptosis and Fas ligand; can induce a chronically-infected macrophage to undergo is the 1 required signal
•• produces IL-2 which is a growth factor for T cells; can also assist the activation of naïve CD8+ T cells
•• produces IL-3 and GM-CSF which induces macrophage differentiation in the bone marrow •• produces lymphotoxin and TNF- which facilitates macrophage binding to epithelium / exit from blood vessel at sites of infection
•• produces macrophage chemotactic factor which causes macrophages to accumulate at sites of infection
once naive CD4 T cells are activated to differentiate into what, they can serve as what?
armed effector TH cells (either TH1 or TH2)
the effector cell that stimulates B cell activation by supplying the 2nd signal of B cell activation
most TH2 effector cells reside where?
in the T cell zones of secondary lymphoid tissues
where they can perform their effector functions
as naïve B cells migrate thru the T cell zones, what occurs?
effector T cells sample the peptide:MHC class II complexes on their surface.
If a helper T cell recognizes its cognate peptide antigen:MHC complex displayed on the surface of a B cell, the effector T cell will do what?
will supply the second signal of activation (includes production of cytokines and CD40 ligand) to the B cell
the remaining effector TH1 cells recirculate thru secondary lymphoid tissues where they can do what?
can activate antigen-presenting B cells
many effector TH1 cells remain in the circulation where they do what?
they patrol and enter tissues at sites of inflammation where they serve as activators of phagocyte activity,
effector TH1 cells produce cytokines that stimulate B cell activation and differentiation into cells that produce what? Why are these important?
antigen-specific antibodies of the IgG1 and IgG3 isotype;
these isotypes are very important opsonizing antibodies (cell-mediated immunity)
Why are the antigen-specific antibodies of the IgG1 and IgG3 isotype important?
these isotypes are very important opsonizing antibodies (cell-mediated immunity)
effector TH2 cells produce cytokines that stimulate B cell activation and differentiation into cells that produce what?
antigen-specific antibodies of the IgG2, IgG4, IgA, and IgE isotypes
Why are the antigen-specific antibodies of the IgG2, IgG4, IgA, and IgE isotypes important?
neutralization and complement fixation, which are important effector mechanisms for clearing extracellular pathogens
T/F CTLs Release Granular Contents in Polarized Fashion
TH1 Effector Cells Activate what? What is the ultimate result?
killing of intravesicular bacteria
Activated Macrophages Become Better what?
APCs and More Bacteriocidal
What acts as the Maestro of Developing Immune Responses?
TH1 Effector Cells
If an activated Th1 cell secretes IFN-y and CD40L, what is the result?
activates macrophages to destroy engulfed bacteria
Th1 secretes FasL or LT, what is the result?
kills chronically infected macrophages, releasing bacteria to be destroyed by healthy macrophages
Th1 secretes IL-2, what is the result?
Induces T cell proliferation thus increasing the number of effector T cells
Th1 secretes IL-3 + GM-CSF, what is the result?
induces macrophage differentiation in the bone marrow
Th1 secretes TNF-a + LT, what is the result?
activates endothelium to induce macrophage adhesion and exit from blood vessel at site of infection
Th1 secretes CXCL2, what is the result?
causes macrophages to accumulate at site of infection
What is the effect of IL-2 on T cells?
What is the effect of IFN-y on macrophages?
increase MHC class I and class II
What is the effect of lymphotoxin(LT) and TNF-B on macrophages?
induces NO production
What is the effect of IL-4 on B cells? T cells?
- growth of IgG1 and IgE
- increase MHC class II induction
hat is the effect of IL-3 on hematopoietic cells?
growth factor for progenitor hematopoietic cells (multi-CSF)
What is the effect of TNF-a on macrophages?
induces NO production
What is the effect of GM-CSF on hematopoietic cells?
increase in production of granulocytes and macrophages and dendritic cells
How is Signaling Thru Cytokine Receptors done?
cytokine receptors consist of at least 2 chains that the cytoplasmic domains bind JAKs
cytokine binding dimerizes receptor to bring together JAKs which activate each other and phosphorylate receptor
transcription factors (STATs) bind to phosphorylated receptors and phosphorylated by activated JAKs
phosphorylated STATs form dimers that move into nucleus to initiate gene transcription
What occurs when a microbe resists destruciton by macrophages? What is the function of this?
function is to prevent dissemination of microbe
Describe a granuloma
multinucleated giant cells that contain mycobacteria are walled of with T cells that cannot be removed