Download T cell activation

‫‪ .1‬فرآیند تولید ‪ IgM‬بصورت غشایی و ترشحی حاصل کدامیک از‬
‫مکانیسم های زیر است؟‬
‫ب) ‪somatic recombination‬‬
‫الف) ‪allelic exclusion‬‬
‫د) ‪different RNA splicing‬‬
‫ج) ‪class switching‬‬
‫‪ .2‬تمامی موارد زیر در مورد بازآرایی قطعات ژنی زنجیره سنگین‬
‫صحیح است‪ ،‬بجز؟‬
‫الف) برخورد قبلی با آنتی ژنی برای این بازآرایی الزم است‬
‫ب) این بازآرایی گاهی منجر به ایجاد زنجیره سنگین نمی شود‬
‫ج) بازآرایی قطعات ژنی زنجیره سنگین بصورت تصادفی است‬
‫د) بازآرایی در قطعات ژنی ‪ V, D, J‬صورت می گیرد‬
Activation of T
lymphocytes
The goal of T cell activation:
1. Is to generate a large number of effector
T cells: to eliminate the stimulating Ag.
2. To produce a population of memory T
cells: to rapidly react with the Ag when
reintroduced.
– From small number of naïve Agspecific
T cells.
Overview of T cell activation
1. Initial activation of naïve T cell occurs mainly in
secondary lymphoid organs.
2. Ag recognition & other activating stimuli, induce
several response:
1. Secretion of cytokine
2. T cell proliferation
3. Differentiation to effector & memory T cells.
3- Effector T cells recognize Ag in lymphoid or
non-lymphoid tissues & are activated to perform
function for elimination of microbes, & in disease
states, for inflammation & tissue damage.
4. Memory T cells are long lived cells with an
enhanced ability to react against the Ag.
5. T cell responses decline after the Ag is
eliminated by effector cells.
Activatin Tofcell
Naïve
and
Effectr
T
activation
cell by Ag
Phases of T cell Responses
Signals for T Cell activation
• T cell activation require: Ag recognition,
Costimulation, and Cytokines.
Recognition of Ag:
Activation of T Cells requires recognition of Ag
presented by Dendritic Cells.
Ag is always the necessary first signal for the
activation of lymphocytes, ensuring that the
resultant immune response is specific for the Ag.
Ag recognition induce a cascade of intracellular
signaling that results to T cell activation.
-Early tyrosine
phosphorylation
events in T cell
activation
T cell signaling downstream of
PLCγ1
The RAS-MAP kinase pathway in
T cell activation
Activation of transcription
factors in T cells
Role of PI3-kinase in T cell responses
Role of Costimulators
Costimulators: Activation of naïve T cells, in
addition to Ag recognition, require signal provided
by molecules on APC, called Costimulators.
The best characterized costimulatory pathway in T
cell activation involves interaction of CD28 on T
cell with B7-1 (CD80) & B7-2 (CD86) on
activated APC.
The B7:CD28 family of Costimulators
 CD28 is a homodimer, each with one Ig domain.
CD28 is expressed on 90% of Th & 50% of Tc
cells (but all mice T cell).
 B7-1 & B7-2 are structurally similar membrane
protein , each with 2 Ig domain. B7-1 is dimmer
but B7-2 is monomer.
• B7-2: is expressed constitutively at low levels, but
increased early after activation of APCs.
• B7-1: is not expressed constitutively and induced
hours or days after activation of APCs.
CD28 Engagement
CD28 signals work in cooperation with Ag
recognition to initiate naïve T cell response.
CD28 engagement results to activation of several
signaling pathways, some of which amplify
signaling from TCR complex & others may be
independent of but parallel to TCR induced signals
Mechanisms
of T cell
activation
• Other Costimulators: ICOS (Inducible Costimulator
(CD278)) is homologous to CD28 is expressed on T
cells. It’s ligand, ICOS-L (CD275) is expressed on DC,
B and Other cells.
• ICOS is required for development and activation of
follicular Th cells, so has essential roll in T-dependent
Ab response.
• Inhibitory receptors: The inhibitory receptors of the
CD28 family are: CTLA4 and PD-1
• The outcome of T cell activation is influenced by a
balance between engagement of activating and
inhibitory molecules of CD28 family.
- Member of
CD28 &B7
family
• Other Costimulatory Pathway: Interaction of
CD40L, expressed on activated T cells, with CD40
which is expressed on DC, B and MФ, activate B
cell and MФ and by this way enhance T cell
activation.
Therapeutic blockade of
Costimulatory
Functional response of T lymphocytes
1. Changes in surface Molecules:
– CD69: its expression increase within a few hrs
after T cell activation. CD69 bind to and reduce
expression of sphangosine 1-phosphate receptor.
– CD25: enables activated T cells to respond to IL-2
– CD40L: Within 24-48 hrs after activation T cells
express high level of CD40L.
– CTLA4: Increase 24-48 hrs after activation.
– Adhesion Molecules: L-selectin & CCR7 but
LFA-1, VLA-4, CD44 and P & E-selectin ligand
Functional response of T lymphocytes
2. IL-2 Secretion and IL-2R expression
IL-2 is a growth, survival, and differentiation factor
for T cells and plays a major role in the regulation of
T cell responses.
1. IL-2 stimulates the survival, proliferation, and
differentiation of Ag-activated T cells.
2. IL-2 is required for the survival and function
of regulatory T cells.
Regulation of IL-2 receptor
expression
Functions of IL-2
 Blockade of IL-2 production has therapeutic usage for
prevention of allograft rejection and therapy of autoimmune
diseases : Cyclosporin A & Tacrolimus (FK506)
3. Clonal expansion of T cells
T cell expansion is mediated by a combination of signals
from the Ag receptor, costimulators, and IL-2.
• Tc cells specific for a microbe increases from 1 in 10*5
to 1 in 3 or 10, and Th cell increase to 1 in 100 or 1000
4. Differentiation of Th Cells into TH1, TH2,
and TH17 Effector Cells
There are 3 distinct subsets of Th cells: TH1, TH2,
and TH17.
 The defining characteristics of these effector cells are
the cytokines they produce & transcription factors
they express.
 The signature cytokines for effector Th cells are:
1. TH1: IFN-γ
2. TH2: IL-4, IL-5 & IL-13
3. TH17: IL-17 & IL-22
Properties of TH1, TH2 and TH17
Development of TH1, Th2 & Th17 subsets
1. TH1, TH2, & TH17 cells all
develop from naive CD4+ T cells,
mainly in response to cytokines
present early during immune
responses.
2. These Cytokines are produced
by APCs (primarily DC and MФ )
and other immune cells ( NK ,
Basophils or Mast cells) present
at the site of the immune
response.
3. Each subset of effector cells
produces cytokines that
promote its own development
and may suppress the
development of the other
subsets.
4. Differentiation of each subset
is induced by the types of
microbes which that subset is
best able to combat.
5. Stimuli other than cytokines
may also influence the pattern
of helper T cell differentiation.
 Differentiated TH1, TH2, and TH17 cells all
develop from naive CD4+ T lymphocytes,
mainly in response to cytokines present early
during immune responses.
 The cytokines that drive the development of
CD4+ T cell subsets are produced by APCs
(primarily Dcs and macrophages) and other
immune cells ( NK , basophils or mast cells)
present at the site of the immune response.
TH1, TH2, and TH17 cells all develop
from
1.
Stimuli other than cytokines may also influence
naive,
the pattern of helper T cell differentiation.
2.
Each subset of differentiated effector cells
produces cytokines that promote its own
development and may suppress the development
of the other subsets.
3. Differentiation of each subset is induced by the
types of microbes which that subset is best able
to combat.
TH 1 Differentiation
 TH1 differentiation is driven
mainly by the cytokines IL-12 and
IFN-γ and occurs in response to
microbes that activate DCs, MФ,
and NK cells.
 IFN- γ and IL-12 stimulate TH1
differentiation by activating the
transcription factors T-bet, STAT1,
and STAT4.
 IFN-γ activate STAT1, which in
turn activate T-bet.
 T-bet promote IFN-γ production through direct
activation of the IFN-γ gene & by inducing
chromatin remodeling of the IFN-γ locus.
 Ability of IFN-γ to stimulate T-bet expression
and the ability of T-bet to enhance IFN-γ, set up a
positive amplification loop for differentiation
toward TH1.
 IL-12 activate STAT4, which further enhance
IFN- γ production.
Mice deficient in IL-12, IL-12R, T-bet or STAT4
can not mount effective TH1 response to
infection.
H 2 Differentiation
 TH2 differentiation is stimulated
by IL-4 and occurs in response to
helminthes and allergens.
 IL-4 stimulates TH2
development by activating
STAT6, and STAT6, together
with TCR signals, induces
expression of GATA-3.
 Mice lacking IL-4, STAT6 or
GATA-3 are deficient in TH2
TH17 Differentiation
 Th17development is stimulated
by pro-inflammatory cytokines
produced in response to bacteria and
fungi.
 Various bacteria & fungi
stimulate production of cytokines like
IL-1, IL-6 & IL-23 by DC.
 Th17 produced not only in
response to bacteria & fungi, but also
with bacteria and fungi infected cell
undergoing apoptosis.
IL-1 & IL-6 promote Th17 differentiation.
TGF-β promote Th17 in the presence of IL-1 &
IL-6.
 Th17 cells produce IL-21 which further enhance
Th17.
But IL-23 involve in proliferation & maintenance
of Th17.
The development of Th17 cells is dependent on
the transcription factors RORγt and STAT3.
IL-4 & IFN-γ inhibit Th17 differentiation.
Differentiation of CD8+ T Cells into
Cytotoxic T Lymphocytes (CTL)
The activation of naïve CD8+T cells requires
antigen recognition and second signals.
The full activation of naïve CD8 + T cells and their
differentiation into functional CTLs and memory
cells may require the participation of Th cells.
Differentiation of CD8 + T cells into effector
CTLs involves acquisition of the machinery to
perform target cell killing.
Two transcription factor involved in CTL induction
are: T-bet & Eomesodermin.
The Role of helper T cells in the differentiation
of CD8+T lymphocytes
Development of Memory T Cells
Properties of Memory T Cells
1. Memory cells survive in a quiescent state and
mount larger and more rapid responses to Ag than do
naïve cells.
2. The number of memory T cells specific for any Ag is
greater than the number of naïve cells specific for
the same Ag.
3. Memory cells express increased levels of anti
apoptotic proteins, which may be responsible for
their prolonged survival. Such as: Bcl-2 & Bcl-XL.
4. Memory cells undergo slow proliferation .
5. The maintenance of memory T cells is depend on
cytokines, but does not require Ag recognition.
– The most important cytokine for maintenance of
memory Th & Tc cells is IL-7.
– Memory Tc cells also depend on IL-15 for survival.
– High expression of IL-7R (CD127) is characteristic of
memory T cell.
6. Their Cytokine genes and other effector
Molecules become accessible, as a result these
cytokines rapidly produced in Ag challenge.
Type of Memory cells
1. Central memory T cells express the CCR7 and
L-Selectin and home mainly to lymph nodes.
They have a limited effector function, but In
response to Ag challenge rapidly proliferate and
generate many effector cells.
2. Effector memory T cells do not express CCR7
or L-selectin and home to peripheral sites,
especially mucosal tissues. On Ag challenge they
produce effector cytokines (IFN-γ) or rapidly
become cytotoxic, but do not proliferate much.