Activation of T and B cells expressing Agspecific receptors results in proliferation Differentiation into effector cells and memory cells The activation of T cells leads to the synthesis and secretion of cytokines that affect many different cell types ID: 910312
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Slide1
Activation and Function Of T and B cells
Activation of T and B cells expressing Ag-specific receptors results in:
proliferation.
Differentiation into
effector cells
and memory cells.
The activation of T cells leads to the synthesis and secretion of cytokines that affect many different cell types.
The activation of B cells results in
Ab
production.
Slide2Activation and Function of T and B cells
Slide3APCs
- dendritic cells
- Macrophages
- B
cells
APCs take up Ag, process and present it to T cells and provide
costimulator
signals
that activate naive T cells.
Dendritic cells express high levels of MHC class II and class I. They are motile moving from sites where they are exposed to Ag to lymph nodes, where they can interact with T cells.
Slide4Fig. shows that the interaction of Ag with dendritic cells in tissues results in the maturation of the dendritic cell, ultimately leading to the Ag-bearing cell moving out of the tissue and to the lymph node draining this tissue site.
In the fig. the Ag "G-bacteria" is taken up by immature
dendritric
cell, Ag interact with toll-like receptors "TLRs" expressed on
dendritric
cells.
Slide5Activation of TLRs by microbial components leads to activation of both branches of immunity "innate and adaptive" through the production of cytokines
*
Toll-like receptors
(TLR) are considered as part of “
pattern recognition molecules
” .
They fit with a distinct pattern of corresponding piece of a pathogen.
They serve as flags alerting responding cells to the presence of invading microorganism.
Slide6They facilitate phagocytosis.TLR activate phagocytes and tissue dendritic cells in response to pathogens.
They are large family of receptors each of which recognizes specific microbial molecular patterns.
Activation of these cells facilitates initiation of acquired immune response due to the production of
proinflammatory
cytokines “ this illustrates the important relationship between the innate and acquired immune system”
Slide7Coating microbes with complement makes phagocytosis
easy”opsonization
”
Foreign
Ags
induce high levels of
costimulatory
molecules while self
Ags
do not induce high levels of
costimulatory
molecules, thus naive T cells are not activated.
Slide8Interactions at the surface of APC and CD4+
T cells
Slide9First signal for T cell activation
Interaction between MHC class II molecules on APC + peptide and "V
+ V
" of TCR on T cell.
This signal is necessary but is not enough for T cell activation.
– Interaction of MHC class II with the co-receptor CD4 which makes T cell
100 fold more responsive to Ag.
CD4 is moved closer to TCR after binding of peptide-MHC to TCR, a process enhancing signal transduction.
Slide103.Costimulator
pairs "B7-CD28, CD152/CD40, CD154".
Costimulator
molecules are required for activation of naive T cells.
CD40-CD154 interaction increases the expression of B7 on APC and enhances B7-CD28 interaction between the APC and the T cell.
4. Adhesion
molecules.
CD54 + ICAM-1 "intercellular adhesion molecule "on APC and CD11a/CD18 = LFA-1 "leukocyte function-associated antigen" on T cell.
Adhesive interactions slow down the movement apart of the APC and T cell.
Slide115. The
Immunological Synapse.
The area of contact between APC and T cell.
The synapse is required for sustained intracellular signaling, lasting until the two cells split apart after 8 hours of contact.
6. T
cells membrane lipids "cholesterol,
glycosphingolipids
" are mobilized to the synapse and draw with them intracellular signaling.
Slide12Slide13Intracellular Events in CD4+
T cell Activation
Slide14Binding of MHC II peptide to TCR transmits a signal via the tightly associated CD3 and Zeta molecule into the interior of the T cell.
The nature of the signal across the membrane may involve aggregation of multiple TCR into the cell membrane
or
a conformational change in the
transmembrane
region of the TCR chain.
Activation of TKs which then activate proteins by adding P group to tyrosine residues.
Slide15TK associated with CD3-zeta = Fyn -
Src
family
TK associated with CD4-zeta =
Lck
-
Sark
family
4. Fyn
,
Lck
activated
they cluster with region of CD3 and zeta chains that contain *ITAMS and phosphorylate them. They act as docking sites for another TK "ZAP 70".
5.
Lck
activated ZAP 70 which phosphorylates adaptor molecules proteins "LAT, SLP-76"
on the cell membrane forming larger complex of signal transduction molecules at the
immuno
-logical synapse.
Slide16Activation of Intracellular Signaling
Activated adaptor molecules activate intracellular signaling pathways.
They bind PLC-
"phosphorylated by ZAP-70" PIP2 "
phosphitidyl
inosital
biphosphate
" DAG "
Diacyl
glyceral
" which activates transcription factor NF-KB.
Slide17*
immunoreceptor
tyrosine-based activation motif.
Activates membrane-associated protein kinase, activate transcription factor NF-KB and IP3 "inositol trip" which increases intracellular
Ca
++
which activates
Calcineurin
which activates transcription factor NF-AT.
This pathway is clinically significant because cyclosporine-A "a drug preventing graft rejection" binds to
calcineurin
and inhibits T cell activation.
Slide18Ras &
Rac
"
guanosine
-nucleotide binding proteins" activate cytoplasmic cascade of mitogen.
Activated protein "MAP" kinase leading to activation of Transcription factor Ap-1.
Activation of genes
enlargement of T cells
IL-2 which is growth factor for T cells & binds to high affinity IL-2 receptor on the same or on different T cell
Slide19Slide20Other ways of T cell Activation
Superantigens
.
Mitogens
Concanavalin
A "Con A" ………
lectin
Phytohemagglutinin
"PHA" ………
lectin
Pokeweed mitogen ………
lectin
Anti CD3 Abs.
CD4
+
T cell subsets
Slide21Slide22TH1
and TH2 are generated from the Ag driven differentiation of THO cells. TH1 cells synthesize IL-2, IFN
and TNF-β(
lymphotoxin
).
Cytokines synthesized by TH1 cells activate cells involved in CMI: CD8
+
T cells, NK cells and M
.
TH2 cells synthesize IL-4, IL-5, and IL-13.
IL-4 and IL-13 influence b-cell class switch to
IgE
IgG4 in humans and IL-5 activates
eosinophils
.
Slide23Viruses and bacteria favor the production of TH1 cells, whereas allergens and parasites favor TH2 cell induction.
Cytokines produced by TH1 can inhibit the function of TH2 and vice versa.
The recently characterized TH17 subset synthesizes IL-17 family cytokines, which induce pro-inflammatory responses in many different cell types. TH17 cells also respond to fungi and some extracellular bacteria.
Slide24Treg cells inhibit the function of the other subsets of CD4+ T cells by cell contact and by the synthesis of inhibitory cytokines TGF- β and IL-10.
Cytokines Influence Differentiation into a particular Subset of CD4+ T Cells(Fig. below).
Slide25Slide26Cytokines synthesized by cells of the innate immune system influence the differentiation into specific subsets of CD4
+
T cells, particularly from dendritic cells. Thus, cells of the innate immune system have a critical role in shaping the pattern of the adaptive immune response. The critical role played by these cytokines is often referred to as a (
third signal
) that works in conjunction of the first
(peptide-MHC-TCR) and second(
costimulatory
) signals in driving the differentiation of activated CD4+ T cells.
Slide27T – B Cooperation
Slide28Slide29Slide30All proteins are thymus dependent "TD"
Ags
, because they require CD4
+
T cells to "help" or cooperate with B cells to synthesize Abs.
The set of CD4
+
cells that participate in
Ab
responses to TD
Ags
is referred to as helper T cells (TH).
T & B cells must be specific for a particular Ag.
Epitopes must be part of the same protein sequence.
Slide31TH and B cells may respond to different epitopes in the antigen; the TH to an internal epitope generated during the processing of the antigen , the B cell to an external epitope.
T – B cooperation in the response to a TD Ag is also known as linked recognition
B cells can act as APC for the CD4
+
T cell "Fig. 10.6".
Slide32Fig10.7:
Interactions between B and T cells are critical for the mutual activation of T and B cells, as a result T cells synthesize cytokines and the B cells synthesize Abs.
CD40-CD40L interactions are required for T and B cell activation and for the B cell to switch from
IgM
synthesis to other
isotypes
.
Slide33Activation of CD8+ T cells
Slide34CD8
+
T cells can kill cells infected with bacteria or viruses, as well as transplanted foreign cells.
CD8
+
T cells recognize a combination of peptide in association with MHC class I molecules.
CD8
+
T cells also synthesize cytokines "IFN-
, TNF-
,
IL-4.
Activation of CD8
+
T cells involve first signal "peptide-MHC-TCR", the second or
costimulatory
signals, in addition of cytokine IL-12"( third signal), this cytokine is synthesized by cells of the innate immune response, it is critical for activation of CD8.
Slide35Slide36The paired adhesion molecules expressed on the T-cell and target cell surface help to maintain contact between the cells for several hours.
Activated CD8
+
T cells contains granules that contain cytotoxic proteins and expresses CD178 "Fas ligand".
Killing by CD8
+
T cells occurs by two pathways
Exocytosis onto target cells "
perforin
and
granzymes
".
Perforin
form
ringlike
transmembrane
channels or pores in the target cell membrane.
Slide37Granzyme
"serine esterase" passes into the cells and induces apoptosis.
Granulysin
is a small protein which can kill intracellular pathogens such as Listeria and Mycobacteria that live inside macrophages and dendritic
cells.
2. Target cell killing via the interaction of the molecule CD178 "Fas ligand" on CD8
+
T cells with CD95 "Fas", a surface molecule expressed on may cells.
Slide383. T
cell can kill itself via Fas
FasL
interactions.
4. Once
T CD8+ cells finishes the killing process, it detaches from the target cell to attack and kill additional
Target cells
.
Harmless or noninfectious
Ags
"killed virus" do not trigger CD8
+
T cells
responses.
Slide39Conjugate Vaccine
Conjugate vaccines utilize the principle of linked recognition to generate TD response. Fig.10.11 shows that a purified polysaccharide from the bacterium is conjugated
i.e
physically linked to a carrier protein. Tetanus toxoid is used in the
H.influenzae
b conjugate vaccine and many others. The carrier protein generates T-cell epitopes that activate T helper cells which interact with B cells specific for the polysaccharide. The resulting TD response involves switching to
isotypes
such as
IgG
and the development of long term memory.
Slide40Slide41Notes:
Two antigen-specific cells , a CD4+ T helper and a B cell, need to interact to generate
Ab
in response to TD
Ags
. The epitopes the T helper and the B cell recognize must be part of the structure of the same Ag(linked recognition).
T-B cell cooperation involves interactions between pairs of molecules on the surface of the CD4+ T cell and the B cell: an Ag specific first signal ( peptide-MHC class II expressed on the B cell with the TCR) and critical second or
costimulator
signals, which
Slide42include CD40-CD40 ligand and ICOS-ICOS ligand. The T cell and the B cell are mutually activated, the T cell to
sythesize
cytokines and the B cell to synthesize Ab. The cytokine synthesized by the T cell determines the
isotype
of the
Ab
sythesized
by the B cell.
Some
Ags
_such as polysaccharides that have many repeating epitopes_ are thymus- independent-TI- and activate B cell
Ab
synthesis without significant T help
Slide43Responses to TI
Ags
are predominantly
IgM
and immunological memory does not develop. People lacking a functional thymus or T cells make responses to TI
Ags
.
The intracellular pathways involved in B cell activation are similar to activation pathways of CD4+ and CD8+ T cells. The signal through the Ag-specific BCR can be modulated positively (via the B cell
coreceptor
) or negatively( for example via the low affinity Fc receptor for
IgG
).