T-cell activation and the two-signal hypothesis
T cells require Ag presentation via trimolecular complex as 1st signal
Other molecular interactions can provide the
2nd required activation signal
Once activated, T cells differentiate into
their effector forms, what are these
CD8+ T cells go on to become killer T
CD4+ T cells differentiate into several
different subsets
Successful T cell-APC interactions organize
signaling molecules into an _______________
___________
immunological synapse
What is the immunological synapse
TCR/MHC-peptide complexes and
coreceptors centralize and form cSMAC
Adhesion molecules/bound ligands
peripherally localize and form pSMAC
What makes up the cSMAC (T cell component and APC component)
T cell- CD28
APC- CD80 (B7-1 and B7-2)
Costimulatory signals are required for
optimal T- cell activation and proliferation. What are these (3 signals)
Signal 1 = Ag-specific TCR engagement
Signal 2 = contact with costimulatory ligands
Signal 3 = cytokines directing T-cell
differentiation into distinct effector cell
types
Positive costimulatory receptors�do what
Negative costimulatory receptors� do what
1. facilitate activation via CD28 and ICOS
2. help turn activation off via CTLA-4, PD-1, and BTLA
What is CD28 and what does it bind to
Molecule expressed on majority of T cells
Markedly enhances TCR-induced
proliferation and survival
Binds to B7-1 & B7-2 expressed by APCs
Generally involved in initial activation
events in T cells
What is ICOS and what does it bind to
Inducible costimulator, binds ICOS-ligand
on activated APCs
What is CTLA-4 and what does it bind to
Induced within 24 hours after activation,
peaks 2-3 days post-stimulation
Binds to B7-1/B7-2 with higher affinity
than CD28, but shuts down signaling
pathways ("putting the brakes on")
What are PD-1 and BTLA-4
PD-1 may help to mediate T-cell
tolerance in nonlymphoid tissues
BTLA may down-regulate inflammatory
Clonal _______ results if a costimulatory
signal is absent
anergy
How does clonal anergy help provide tolerance
If only signal 1 is received, the cell is
rendered nonresponsive
This might happen if a T cell isn't
screened against a peripheral self antigen during development
IL-2 is an example of an _________ type of
cytokine response system
Activating
What is an activating cytokine response system
T cells produce the cytokine and receptor
Binding of this ligand induces a very
strong proliferation signal during
activation stages
What cells can activate T cells
Dendritic cells, macrophages, B cells
What are superantigens
a special class of T-cell activators
(Viral/bacterial proteins that bind to specific
V? regions of TCRs and ? chain of class II
MHC molecules)
Super antigens "short circuit" the need for what
costimulation
What dramatic response do super antigens produce
cytokine response by large proportion of inappropriately activated T cells
Exogenous vs endogenous superantigens
Exogenous�soluble proteins secreted
by bacteria
Endogenous�cell membrane proteins
generated by viral genes integrated into
mammalian genomes
Initial activation signals 1 and 2 induce what in T cells
Upregulation of prosurvival genes
Transcription of IL-2 and IL-2R genes
Outcome is activation and
robust proliferation
What happens in T cells following activation
Cell cycle entry and chromatin condensation
What are are the five subsets of T helper cells
TH1 and TH2
TH17
TREG
TFH
How is each T helper subset unique
produces a distinct cytokine profile
and regulates distinct activities within the
body
Differentiation of T helper cell subsets is
regulated by what
polarizing cytokines
APCs may bind ________via PRRs,
inducing cytokine secretion
(Different PRRs engaged (via
different antigens) = different
cytokines produced)
PAMPs
Where do polarizing cytokines come from and what do they trigger
APCs, trigger MG regs and create effector cytokines
Effector T helper subsets are distinguished
by what three properties
Distinct polarizing cytokine set that
induces expression a master gene regulator that regulates expression of a signature set of effector cytokines produced by that subset
What molecules induce TH1 differentiation
IL-12, IL-18, and IFN-y induce TH1
differentiation
What does IFN-y production do
Leads to class switching to IgG
classes that support phagocytosis
and complement fixation
Supports differentiation of antiviral
IL-4 promotes TH2 subset differentiation, how so
Triggers master regulator GATA-3 to
upregulate characteristic IL-4, IL-5,
and IL-13 production
IL-4 acts to promote activities of
eosinophils against __________
IL-4 induces class switching to ____,
which helps other cell types to
release anti-parasite inflammatory
Helminths
IgE
Class switching: IFN-? from TH1 responses inhibits what
IgG1/IgE class switching (a common TH2-
induced response)
Class switching: IL-4 from TH2 responses inhibits what
production of IgG2a (a common TH1-
induced response)
Class switching: IL-10 from TH2 responses also inhibits what
TH1 responses by suppressing the production
of inflammatory mediators from APCs
Master regulators commit T cells to one
subset or the other
T-Bet suppresses _____ pathway gene
expression
GATA3 suppresses ______ pathway
gene expression
TH2
TH1
TH-17 cells
Activation in the presence of _____ and
________ forms this subset
_____ also plays a role in finalizing the
subset commitment
master regulator _____
IL-6, TGF-beta
IL-23
ROR?
(induced) TREG cells
Similar in function to ___________________
originating in the thymus
natural TREG cells
(induced) TREG cells
Arise during activation of T cells in the
presence of __________
TGF-? induces ______ master regulator,
shifting activating cells into this subset
iTREG cells secrete __ and ___ to
downregulate inflammation (by inhibiting
APCs) and su
TGF-?
FoxP3
IL-10 and TGF-?
TGF-? is a key cytokine for differentiation of
both subsets TH17 and TReg
_____ is the "switch," allowing ROR?t to
dominate and induce ____ subset
differentiation instead
IL-6
TH17
TFH helper cells, ______ and ______ appear to be the polarizing cytokines
IL-6 and IL-21
In TFH helper cells, IL-6 and IL-21 lead to activation of _______ master regulator. This also inhibits _________ expression
Bcl-6
T-Bet, GATA3, and ROR?t
IL-4 and IL-21 are characteristic secreted
cytokines by TFH cells, promoting ______ differentiation
B-cell
L-2, TGF?, and IL-4 play roles in
polarizing na�ve T cells to ________ cells
TH9 cells
Transcription factors _______ and ________
drive TH9 differentiation
IRF-4 and PU.1
TH9 cells produce ______ in expelling
worms and contributes to antitumor
responses
IL-9
TH22 Cells
� IL-6, IL-23, and TNF polarize na�ve T
cells to TH22 cells by upregulating ______________
AHR
transcription factor
TH22 effector cytokine is ____________
IL-22
How are TH22 cells distinct from TH17 cells
distinct from TH17 cells in that TH22 do
not express ROR?t or make IL-17
TH22 secrete _________ and express
___________ for skin
IL-13
homing receptors
Early in differentiation, TH subpopulations
may be able to shift
When exposed to IL-12, young TH2 cells
will produce _______
Young TH1 cells will produce _______ in TH2
polarizing conditions
Neither TH1 or TH2 can adopt ______ or ____ traits
IFN-?
IL-4
TH17 or iTREG traits
Leprosy
Tuberculoid stimulates ____ responses
Lepromatous stimulates ______
responses; not as effective at
clearing the disease
TH1
TH2
HIV progression to AIDS possibly influenced
by a shift from _____ to ______ responses over
time
TH1 to TH2
Virally produced IL-10 homolog in EBV
infections may reduce _____ responses,
conferring a survival advantage
TH1
Na�ve, effector, and memory T cells display
broad differences in surface protein
expression
Three surface markers can differentiate
the sets, what are these
CD44�increases in response to
___________ signals
CD62L�an ____________ protein
CCR7�a _____________ receptor
TCM and TEM are distinguished by their locale
and commitment to effector function
TCM cells�_________ memory T cells
...
TCM cells
reside in/travel between ___________
lymphoid tissues
Live longer/divide more times than ____
cells
Are rapidly reactivated by ________
Can differentiate into several subset types
depending on ______________________
secondary
TEM
second Ag exposure
cytokine environment
TEM cells�___________ memory T cells
Travel to/between _________ tissues
Contribute better to ________ defenses
Shift right back into _________ functions on
second Ag exposure
tertiary
first-line
effector
TRM cells - permanent residents of
_________________ tissue
Respond upon ___________
_______ TRM found in multiple tissues
previously infected
reinfection
CD8+
How and when do memory cells arise?
Ongoing studies, but currently indicate/
hypothesize that:
Memory cells may arise very early in
immune response (____ days)
_______ cells may arise from or prior to _____
TEM cells may be derived from fully
differentiat
3
TCM, TEM
effector
asymmetrical division
T-cell activation
What signals induce memory cell
commitment?
Unclear but ________ help seems to be required
More ___________, better memory pool
T-cell
proliferation
Do memory cells reflect the heterogeneity of
effector cells from a primary response?
Unclear�memory cell response appears
diverse, where does that diversity come from
Maybe that diversity is from the original
response, or is it generated anew from
response to different environmental
cues during rechallenge? Perhaps both.
Are there differences between CD4+ and
CD8+ memory T cells?
Maybe
More memory CD8+ T cells than CD4+,
but they proliferate more during their
responses
Could also be due to differences in
life span of different memory T-cell
types
How are memory cells maintained over
many years?
Unclear, but they seem to persist for
years in the absence of Ag
Memory persistence seems to depend
on cytokine input to induce occasional
cell divisions
IL-7 and IL-15 appear important to
this homeostatic proliferation