Transcript Antigen Presentation by B cells

T Cell Activation/Function
Ned Braunstein, MD
[email protected]
[email protected]
The Major T Cell Subsets
CD4+ T cells
p56 lck
z z
g d e
Ca Cb
CD4
CD8+ T cells
p56 lck
Va
Vb
MHC II
z z
g d e
CD3
TCR
peptide
(1) Interacts with MHC class II expressing cells
(B cells, macrophages)
(2) Induce(help) B cells to synthesize antibody
(3) Induce and activate macrophages
(4) Secretes lymphokines
Ca Cb
CD8
Va
Vb
MHC I
CD3
TCR
peptide
(1) Interacts with MHC class I expressing cells
(all nucleated cells)
(2) Kill MHC class I expressing target cells
(3) Suppress immune responses
(4) Secretes lymphokines
Naïve T cells are activated by antigen in LNs where they
mature into effector cells
(1) Naive T cells home continuously from the blood to lymph nodes and other
secondary lymphoid tissues. Homing to lymph nodes occurs in high endothelial
venules (HEV), which express molecules for the constitutive recruitment of
lymphocytes.
(2) Lymph fluid percolates through the lymph nodes; the fluid is channeled to
them from peripheral tissues, where dendritic cells collect antigenic material. In
inflamed tissues, dendritic cells are mobilized to carry antigen to lymph nodes,
where they stimulate antigen-specific T cells. On stimulation, T cells proliferate
by clonal expansion and differentiate into effector cells, which express receptors
that enable them to migrate to sites of inflammation.
(3) Although most effector cells are short-lived, a few antigen-experienced cells
survive for a long time. These memory cells are subdivided into two populations
on the basis of their migratory ability: the effector memory cells migrate to
peripheral tissues, whereas central memory cells express a repertoire of homing
molecules similar to that of naive T cells and migrate preferentially to lymphoid
organs.
The Biology of Dendritic Cells: Antigen capture and presentation to T cells
Antigens are captured by DCs in peripheral
tissues and processed to form MHC-peptide
complexes. As a consequence of antigen
deposition and inflammation, DCs begin to
mature, expressing molecules that will lead
to binding and stimulation of T cells in the Tcell areas of lymphoid tissues. If the antigen
has also been bound by B cells, then both B
and T cells can cluster with DCs. After
activation, B blasts move to the lining of the
intestine, the bone marrow, and other parts
of the lymphoid tissue with some becoming
antibody-secreting plasma cells. T blasts
leave the blood at the original site of antigen
deposition, recognizing changes in the
inflamed blood vessels and responding
vigorously to cells that are presenting
antigen. This limits the T-cell response to the
site of microbial infection. Banchereau, J.
and Steinman, R. Nature 392, 245 - 252
(1998)
The T cell activation cycle
Minutes
Hours
Days
IL-2R
P
P
Ca++
IP3
DAG
Antigen
recognition
c- fos
c- jun
c- myc
NF-KB
NF-AT
Immediate
events
IL-2 etc.
Cytokine production and
autocrine stimulation
Effector functions:
Help
DTH
Killing (CTL)
regulation
Proliferation
MHC + Ag
ICAM-1 (CD54)
CD80
LFA-1
(CD11a/CD18)
CD4
CD3
CD28
IL2R
CD45
lck
fyn
ZAP-70
PTK
RAS
Cytoplasm
PLC
PIP2
PKC
DAG
IP3
MAPkinase
Ca
Nucleus
NF-AT
NF-KB
OTF1
IL-2
MHC + Ag
CD80
ICAM-1
(CD54)
LFA-1
(CD11a/CD18)
CD4
CD3
CD28
IL2R
CD45
lck
fyn
ZAP-70
PTK
RAS
Cytoplasm
PLC
PIP2
DAG
PKC
IP3
Ca2+
I-kB
P
NF-kB
Nucleus
NF-AT
NF-kB
OTF1
IL-2
MAP kinase
MHC + Ag
CD80
ICAM-1 (CD54)
LFA-1
(CD11a/CD18)
CD4
CD3
CD28
IL2R
CD45
fyn
ZAP-70
lck
PTK
Cytoplasm
PLC
CNB
PIP2
PKC
DAG
IP3
Ca2+
CNA
Calmodulin
P
NF-AT
Nucleus
Jun Fos
P
NF-AT
NF-kB
OTF1
IL-2
The T cell activation cycle
Minutes
Hours
Days
IL-2R
P
P
Ca2+
IP3
DAG
Antigen
recognition
c- fos
c- jun
c- myc
NF-kB
NF-AT
Immediate
events
IL-2 etc.
Cytokine production and
autocrine stimulation
Effector functions:
Help
DTH
Killing (CTL)
regulation
Proliferation
Key molecular interactions between T cells
and APCs
CD3
TCR
MHC class II/
autopeptide
CD40
CD80
Activated T cell
CD40
CD40L
CD28
CD40
CD80
MHC
class II
(1) induction of cytokines/chemokines (IL-8, IL-12, TNF-a, MIP-1a)
(2) stimulation of CD80 and CD86 expression and co-stimulatory
function with activation of T cell growth
(3) augmentation of antigen-presenting function
Naïve CD4+ T cells differentiate into Th1 and
Th2 subsets
Th1 Cells
IL-2
IFN-g
TNF
IL-2
Antigen +
APC
Resting
CD4+ cell
“pTh”
IFN-g
(–)
IL-4
IL-10
(–)
IL-4
IL-5
IL-6
IL-10
Activated
CD4+ cell
Th2 Cells
Functions of Th subsets
Functions of Th1 subsets
Th1 Cells
IL-2
IFN-g
TNF
IFN-g
(–)
IL-4
IL-10
(–)
• Activate macrophages/dendritic cells
augment antigen presentation
• induce delayed type hypersensitivity
(DTH) responses important in
eradicating intracellular pathogens
(TB, leprosy, listeria
• mediate Th1 diseases (ie; rheumatoid
arthritis, multiple sclerosis and type I
diabetes
Functions of Th2 subsets
IL-4
IL-5
IL-6
IL-10
Th2 Cells
• Help B cells and induce humoral
immunity
• mediate allergic and immediate
hypersensitivity responses
• involved in antibody mediated immune
diseases like SLE and ITP
Major Functions of T Lymphocytes
(1) Induction and Activation of B cells (Help)required for most antibody responses
(2) Delayed Type Hypersensitivity (DTH) - important
in elimination of intracellular pathogens (virus,
fungi and mycobacteria)
(3) Cell mediated Cytotoxicity (Killer function)important in the immune response to virus
infected cells and cancer cells
(4) Suppressor Cell Functionregulates the cell mediated and antibody
responses
The Induction and Activation of B cells
(Helper Function)
Antigen binds specifically to SmIg, is internalized into
vesicles and cleaved into peptides which displace CLIP
and bind to MHC class II molecules in the endocytic
compartment. The peptide/MHC complex is then
transported to the surface membrane.
The CD4+ T cell a,b TCR/CD4 complex binds to the MHC
class II/peptide complex on the surface of B cells. The
CD4+ Th2 cells are triggered to secrete IL-2, IL-4, IL-5,
IL-6 and IL-10 and begin to express CD40L. These
lymphokine and contact dependent signals (CD40L) induce
B cells to proliferate, class switch and differentiate into
antibody (IgM, IgG, IgA and IgE) secreting B cells and
plasma cells.
Antigen Processing and Presentation by B cells
ANTIGEN
BCR
(SmIg)
MHC Class ll
B cell
Peptide
Antigenic peptides
Bind to MHC class II
molecules
Internalization
of antigen/Ig
Antigen binds specifically to BCR (surface membrane
Ig), is internalized into vesicles and cleaved into peptides
which displace and bind to MHC class II molecules. The
peptide/MHC complex is then transported to the surface
membrane.
Antigen Presentation by B cells
BCR
(SmIg)
hapten
Antigen
MHC class II
carrier protein
MHC class II/
carrier peptide
complex
B cell
carrier peptides
Antigen binds specifically to SmIg, is internalized
into vesicles and cleaved into peptides which
displace and bind to MHC class II molecules. The
peptide/MHC complex is then transported to the
surface membrane.
Expression of Membrane Proteins Following
Antigen Specific Activation of T and B Cells
BCR
(SmIg)
TCR
MHC
class II CD4
Resting
B cell
BCR
(SmIg)
Resting
Effector
T cell
CD23
IL-2R
MHC class II
Activated B cell
CD40
CD80
CD86
CD40L
TCR
CD4
MHC class II
Activated
Effector
T cell
CONSEQUENCES OF CD40L/CD40 INTERACTIONS DURING
T-B CELL INTERACTIONS
CD23
CD40L
Sm Ig
CD40
Activated B Cell
TCR
CD4
Activated Effector T cell
Triggering of B cell proliferation
Rescue from apoptosis
Induction of Ig isotype class switching
Up-regulation of CD80 and CD86
Germinal center formation
Up-regulation of CD23
Downregulation of CD40L expression
Final Phases of B cell Differentiation are Mediated by
Contact T cell signals (CD40L/CD40) and Lymphokines
CD23
CD40L
TCR
SmIg
CD4
CD40
Activated Effector T cell
Activated B cell
Lymphokines
IL-2, IL-4, IL-5, IL-6, IFN-g, TGFb
IgG
IgA
IgE
Plasma Cell
The Hyper IgM Syndrome (HIM)
The Hyper IgM Syndrome (HIM) is an X chromosome-linked Ig
deficiency characterized by low serum levels of IgG, IgA and IgE
with normal numbers of circulating IgM expressing mature B cells.
Germinal centers and splenic follicles due not develop.
Affected patients (usually males) are susceptible to pyogenic
infections, autoimmune disease and lymphoproliferative disease.
In addition, patients are also susceptible to Pneumocystis carini
infections.
The genetic defect in the majority of HIM patients is associated
with mutations in the gene encoding CD40L and can be corrected
functionally by soluble CD40 ligand, in vitro. A few HIM patients
have normal CD40L but defects in CD40 signaling.
Major Functions of T Lymphocytes
(1) Induction and Activation of B cells (Help)required for most antibody responses
(2) Delayed Type Hypersensitivity (DTH) - important
in elimination of intracellular pathogens (virus,
fungi and mycobacteria)
(3) Cell mediated Cytotoxicity (Killer function)important in the immune response to virus
infected cells and cancer cells
(4) Suppressor Cell Functionregulates the cell mediated and antibody
responses
Delayed Type Hypersensitivity (DTH)
a. DTH is initiated principally by CD4+ Th1 cells and is the
primary defense mechanism against intracellular parasites
including the mycobacteria (TB), fungi and intracellular
bacteria (listeriae monocytogenes).
b. The cognitive phase of DTH involves CD4+ T cell macrophage/dendritic cell (MHC class II/peptide)
interaction resulting in the local secretion of lymphokines.
c. The effector phase of DTH is effected by lymphokines
which activate macrophages to secrete lysozyme, TNF, IL1 and IL-12 as well as chemotactic and migration
inhibitory factors restricting granulocytes, macrophages
and eosinophils to the site of inflammation.
DTH Pathway of Contact Hypersensitivity
Th1 CD4+ T Cells Induce Inflammation and DTH
APC
Activated CD4+ Th1 cell
CD4
TCR
CD4+ Th1 cell
CD40L
CD40L
CD40
CD40
dendritic cell
Macrophage/
mesenchymal cell
Inflammation inducing
CD40L/CD40 interactions
Activated macrophages,
mesenchymal cells and
endothelial cells
activated
dendritic cell
Proinflammatory molecules
Chemokines (IL-8, SDF-1)
Lymphokines (IL-1, GM-CSF,TGFb
IFNb, IL-12, IL-6
NO, proteolytic enzymes, PGE2
T Cell- Macrophage Interactions
Fc receptor
TCR a,b
MHC class II
CD3
CD4
CD4 Th1 Cell
CD28
Macrophage
B7 (CD80)
IL-2
IL-12
CD40L
CD80
TCR a,b
CD4
IL-2
Receptor
MHC II
IFN-g
CD28
Activated Th1 Cell
CD80
IL-1
IL-6
IL-12
TNF
TGF-b
cytotoxic granules
Activated Macrophage
Physiology of the DTH Response
CD2
MHC II/peptide
Antigen/IgG
TCR a,b
Phagocytosis
killing
CD4+ TH1
T Cell
Fc Receptor
CD4
IL-12
IL-2
Macrophage/
Dendritic cell
TCR a,b
IL-1, TNF, IL-6
IFN-g
IL-2R
CD4
fibroblasts
endothelial cell
hypothalamus
granulocytes
IL-3, IL-8
Mast Cell
Eosinophil
IL-3, IL-4, IL-5
fever
Functions of Th subsets
Functions of Th1 subsets
Th1 Cells
IL-2
IFN-g
TNF
IFN-g
(–)
IL-4
IL-10
(–)
• Activate macrophages/dendritic cells
augment antigen presentation
• induce delayed type hypersensitivity
(DTH) responses important in
eradicating intracellular pathogens
(TB, leprosy, listeria
• mediate Th1 diseases (ie; rheumatoid
arthritis, multiple sclerosis and type I
diabetes
Functions of Th2 subsets
IL-4
IL-5
IL-6
IL-10
Th2 Cells
• Help B cells and induce humoral
immunity
• mediate allergic and immediate
hypersensitivity responses
• involved in antibody mediated immune
diseases like SLE and ITP