03/06c T Cells Flashcards
What four events are required for T cell priming?
1) Antigen capture by dendritic cells
2) Activation of dendritic cells
3) Co-localization of dendritic cells and naive T cells at lymphoid tissues
4) Cross-talk and activation signals between dendritic cells and T cells
What are the three components of activating cross-talk between DCs and T cells?
Antigen presentation (signal 1)
Co-stimulatory molecules (signal 2)
Cytokines
How are newly-activated T cells retained in the lymph node?
Activated T cell downregulate expression of S1P receptors
S1P is a chemotactic lipid that normally promote T cell egress from the lymph node
It takes several days for the trapped antigen-specific T cell to proliferate, differentiate, and re-express S1P receptors
What molecules mediate initial binding of a T cell with an APC? What is their mechanism of action?
T cell adhesion molecules LFA-1 and CD2
Form an initial low-affinity binding, long enough for TCRs to interact with peptide-MHC complexes
When TCRs become activated, this signals a conformational change in LFA-1 and promotes a longer binding
If the TCR is NOT activated, the T cell will let go and continue sampling other APCs
What is the Immunologic Synapse?
Interaction between LFA-1 and ICAM-1, and TCRs with MHC-peptide complexes
What is Signal 1?
Binding of TCRs to MHC-peptide complexes
What is Signal 2?
Stimulation of CD28 on T cells by B7-1 and B7-2, which promotes T cell activation, proliferation, and survival via IL-2
What is IL-2?
Major T cell growth factor - necessary for growth, proliferation, and differentiation of T cells to become effector cells
Produced mainly by CD4 T cells
Also used therapeutically in chemotherapeutics and immunosuppressive drugs
What are the effects of Signals 1 and 2?
Stimulate the expression of IL-2 and IL-2 receptors
Stimulate the survival, proliferation, and differentiation of T cells
What happens if a naive T cell sees Signal 1, but not Signal 2?
Leads to tolerance induction or anergy - important for maintaining peripheral tolerance of the host
What is the function of CTLA-4?
Induced on activated T cells and binds to B7 more avidly than CD28
Delivers inhibitory signals to activated T cells to help terminate the T cell response
In what applications is CTLA-4 used therapeutically?
Treatment of rheumatoid arthritis
To extend graft survival
Treatment of melanoma
What are the helper activities of CD4 cells?
Express cytokines that allow them to activate other cells
Major example - CD40 ligand binds CD40 on APCs - makes them more potent by increasing their expression of B7 molecules, cytokines, and other activators
What are the effector functions of Th1 cells?
Stimulate macrophages through production of IFN to make them more efficient at phagocytosis and destruction of virus-infected cells
What are the effector functions of Th2 cells?
Drive IgE production and mobilize eosinophils from the bone marrow to destroy helminths
What are the effector functions of Th17 cells?
Secrete IL-17 and recruit lots of neutrophils to clear extracellular bacteria and fungal infections
What diseases are associated with Th1 cell responses?
Autoimmune disorders
Tissue damage due to cytokine storm
What diseases are associated with Th2 cells?
Allergic diseases (e.g. asthma)
What diseases are associated with Th17 cells?
Organ-specific autoimmune disorders such as rheumatoid arthritis and multiple sclerosis
What is Signal 3?
Cytokines provided by APCs
Specific cytokines dictate what type of effector T cell will result from differentiation
Cytokines produced by polarized T cells can also promote further polarization of the same cell type, and inhibit polarization of other cell types (positive and negative feedback)
Which cytokines are associated with Th1 cell differentiation?
IL-12
IFN gamma
Which cytokine is associated with Th2 cell differentiation?
IL-4
Which cytokines are associated with Th17 cell differentiation?
TGF-beta
IL-6
How long do T cells remain polarized? What is the function of this?
A long time (indefinitely?); will express the same cytokine when restimulated
Allows cells to quickly start making cytokines and mount the appropriate immune response the next time it encounters the pathogen
What are the main effector functions of Th1 cells?
Activate macrophages to ingest and destroy microbes
Produce mainly IFN gamma; also IFN and other chemokines to contribute to leukocyte recruitment and enhanced inflammation
What are the major functions of IL-12?
Induce Th1 cell differentiation and T cell production of IFN and TNF
Inhibit differentiation of Th2 cells
Enhance cytotoxic activity of NK cells and CTLs
What are the major functions of IFN-gamma?
Inhibits viral replication
Activates macrophages to kill phagocytosed microbes
Promote NK activity
Act on B cells to promote class switching between certain IgG subclasses
Promote antigen processing and MHC expression
What cell types make IFN-gamma?
Th1 cells
CTLs
NK cells
NKT cells
How do CD4 Th1 cells activate macrophages?
Upregulate CD40 ligand and secrete IFN
CD40 ligand binds CD40 on macrophages and upregulates expression of IFN receptor
IFN activates the macrophage to kill phagocytosed bacteria and stimulate inflammation
What are the two general types of macrophages? What are their functions?
M1 macrophages kill phagocytosed bacteria (generated early in infection, stimulated by IFN)
M2 macrophages inhibit inflammation, clean up, and repair damaged tissue (generated as infection resolves)
What are the major effector functions of Th2 cells?
Stimulate IgE- and eosinophil-mediated reactions against helminthic infections
Produce IL-4, IL-5, IL-13, and IL-10
Block entry and promote expulsion of microbes from mucosal organs
Stimulate alternative macrophage (M2) activation for tissue repair
What are the main functions of IL-4? Name four
Stimulates production of IgE by B cells
Stimulates gut peristalsis to clear the parasites
Stimulates recruitment of eosinophils
Contributes to M2 macrophage activation
What are the main functions of IL-13? Name three
Increases mucous secretion in the gut and airways
Stimulates recruitment of eosinophils
Contributes to M2 macrophage activation
What is the main function of IL-5?
Activates eosinophils
What is the main function of IL-10?
Major anti-inflammatory cytokine - suppresses immune responses at the site of infection, after the infection has resolved
Downregulates expression of Th1 cytokines
What are the main effector functions of Th17 cells?
Induction of neutrophilic inflammation against acute extracellular bacteria and fungi
Produce IL-17, which induces neutrophil infiltration and the production of antimicrobial substances
What are the main effector functions of CD8 T cells (CTLs)?
Eliminate intracellular microbes by destroying infected cells (stop the spread of virus by eliminating the reservoir of infection)
Recognize target cells through MHC I, and secrete cytotoxic proteins (perforin and granzyme) into an immunologic synapse so that they cannot diffuse to nearby cells (specific recognition)
Also produce Fas Ligand to induce apoptosis
Produce IFN and TNF to activate macrophages
How do effector T cells differ from naïve T cells? List five general ways
Express different adhesion molecules - lose L-selectin
Express different chemokine receptors - gain inflammatory chemokine receptors
Circulate differently, and home to sites of inflammation rather than secondary lymphoid organs
Show increased sensitivity for antigen
Have less stringent activation requirements (Signal 1 only)
What are the three phases of T cell response?
1) Initial expansion of effector cells as they search for antigen
2) Contraction and homeostasis as infection is controlled
3) Memory - increased number of antigen-specific T cells circulating
What are the major defining properties of memory T cells?
Ability to survive in a quiescent state after antigen is eliminated
Ability to mount a larger and more rapid response to antigens than naive T cells
