Lecture 13: Differentiation and Functions of CD8+ T Cells Flashcards
% of helper T cells and % of cytotoxic T cells out of T lymphocyte population
66% Helper T cells
33% Cytotoxic T cells
Activated CTLs contain
Lysosomes that contain perforin and granzymes
T-bet regulates what
Transcription of genes encoding perforin, granzymes and IFN-y
How do some EC antigens get presented in association with MHC I molecules?
Cross presentation- some viral Ags are released from phagosome in cytoplasm of DC and then presented with class I MHC (The same cross-presenting APC can display microbial peptides within class II MHC for CD4+ T cells)
Why does generation of CD4+ T effector cells precede appearance of CD8+ T cells
Because DCs need “education” which takes time.
Licensing of APC occurs when
CD4+ T cell delivers activating signals through CD40L/CD40 signaling and release of IFN-y to DC after it recognizes Ag presented by an MHC class II APC
Activated CD4+ T cells increase expression of
CD40L
Effect of CD40L/CD40 and IFN-y interactions
Upregulates expression of CD80/86 on DC and stimulates Ag cross presentation which makes them more efficient at inducing differentiation of CD8+ T cells
IL-2R shares the same y chain with what cytokines
IL-15R and IL-21R
Naïve CD8+ T cells proliferate in response to ___ and ___ signals, but also require ___ or___ for survival and development of optimal effector functions
Proliferate in response to TCR and CD28 signals, but also require IL-12 or IFN-y
IL-15 produced by what and is required for
DCs and tissue macrophages
Survival of memory CD8+ T cells
IL-21 is produced by what and plays a role in
Activated CD4+ T cells
Induction of CD8+ T cell memory and prevention of CD8+ T cell exhaustion
Key feature of IL-2
Autocrine loop through which it operates
15kDa peptide
Local release of IL-2 can lead to
Clonal expansion of T cells, which upon recognition of Ag presented by APC express a-subunit of IL-2R
Local release of IL-2 by activated CD4+ T cell leads to
Activation of nearby Ag-activated CD8+ T cells in a paracrine fashion
IFN-y is a ___dimer
Homodimer of 25kDa
IFN-y has ability to increase __________ expression on a range of cell types and induce expression of ______ on professional APCs
Increase MHC I expression on many cells
Induce expression of MHC II on professional APCs
IFN-y favors development of ___ and ___ cells and biases production of Ig ___ and away from Ig___
Favors development of Th1 cells and B cell differentiation
Production towards IgG and away from IgE
IL-12 promotes production of pro-inflammatory cytokines
IFN-y and TNF-b by CD4+ and CD8+ T cells
IL-12 stimulated CD8+ T cells compared to IFN-y stimulated T cells
IL-12 stimulated are more effective in controlling tumor and they maintain high numbers and function as compared to IFN-y stimulated cells
IL-12 also assists in prevention of ___ and activates
Prevents exhaustion of CD8+ T cells
Activates NK cells
Primary source of IL-15
Activated tissue macrophages and mature DCs
Exogenous IL-15 favors human ____ differentiation
Th1 T cell differentiation
IL-15 stimulates proliferation of ____ and ___
Memory CD4+ and CD8+ and naïve CD8+ T cells
IL-15 costimulates innate immune ____ production
IFN-y
IL-21 role with B cells and T follicular help cells
Key role in B cell differentiation to plasma cells and in development of T follicular helper cells
IL-21 effect on CD8+ T cells
Induces a functional program that leads to enhanced survival, antiviral activity and antitumor activity
IL-21 role with Th17 cells
Key role in development of Th17 cells
IL-21 promotes a range of _____ diseases
Autoimmune diseases, including lupus, type I diabetes, MS, IBD and psoriasis
Clinical trials using IL-21 inhibitors are in progress
What happens after DCs present viral Ags to CD8+ T cells
They differentiate into CTLs and release TFN-b, IFN-y, perforins and granzymes
Exhausted CD8+ T cells show what
Reduced expression of IFN-y and increased expression of PD-1 inhibitory receptors
Fas ligand is expressed on what cells
Activated CTLs, and engages Fas on the surface of target cells, inducing apoptosis
Perforin and granzymes
Released from CTLs and enter target cells. Granzymes are delivered into cytoplasm of target cells by a perforin-dependent mechanism
Fas ligand process in type I cells
FasL binds Fas and recruits procaspase 8 through the FADD adaptor, then converts it to active caspase 8
- In Type I cells caspase 8 can directly cleave caspase 3, independent of mitochondria
- Activated Caspase 3 activates CAD via degradation of ICAD
- CAD causes DNA degradation in nucleus
Fas ligand process in type II cells
- FasL binds Fas, procaspase 8 is activated
- Caspase 8 cleaves Bid which stimulates release of Cytochrome C from mitochondria
- Cytochrome C, along with Apaf-1 and ATP, activate caspase 9, which activates caspase 3
- Caspase 3 activates CAD via degradation of ICAD
- CAD destroys DNA in nucleus
Granzyme mediated apoptosis
TCR recognizes specific Ag within class I MHC CTL and target cell form immunologic synapse and perforins/granzymes are released, killing only the infected cell
Granzyme B
Only granzyme shown to be required for CTL cytotoxicity in vivo
It activates Caspase-3 which triggers apoptosis
Perforin is homologous to
C9 complement protein
