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The Major T Cell Subsets
V
C C
V
peptide
CD3
TCRCD4
MHC II
V
C C
V
CD3
TCR
p56 lckp56 lck
MHC I
CD8
(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
(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
CD4+ T cells CD8+ T cells
peptide
(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.
Naïve T cells are activated by antigen in LNs where they mature into effector 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 T-cell 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 Biology of Dendritic Cells: Antigen capture and presentation to T cells
Ca++IP3DAG
PP
c- fosc- junc-mycNF-KBNF-AT
Antigenrecognition
Immediateevents
Cytokine production and autocrine stimulation
Proliferation
Minutes Hours Days
The T cell activation cycle
IL-2 etc.
IL-2R
Effector functions:HelpDTHKilling (CTL)regulation
CD4CD3
MHC + Ag
ICAM-1 (CD54)
LFA-1 (CD11a/CD18)
lckfyn
IL-2
CD45
PTK RAS
PLC
PIP2IP3
Ca
DAGPKC
NF-AT NF-KB OTF1
Nucleus
Cytoplasm
CD28IL2R
ZAP-70
MAP-kinase
CD80
CD4CD3
MHC + Ag
ICAM-1(CD54)
LFA-1(CD11a/CD18)
lckfyn
IL-2
CD45
PTK RAS
PLC
PIP2
IP3
Ca2+
DAGPKC
NF-AT NF-B OTF1
Nucleus
Cytoplasm
CD28IL2R
P I-B
NF-B
ZAP-70
MAP kinase
CD80
P
NF-AT
FosJun
CD4CD3
MHC + Ag
ICAM-1 (CD54)
LFA-1(CD11a/CD18)
lckfyn
IL-2
CD45
PTK
PLC
PIP2
IP3DAGPKC
NF-AT NF-B OTF1
Nucleus
Cytoplasm
CD28IL2R
CNB
Cal-modulin
CNA
ZAP-70
CD80
Ca2+
P
Ca2+
IP3DAG
PP
c- fosc- junc-mycNF-BNF-AT
Antigenrecognition
Immediateevents
Cytokine production and autocrine stimulation
Proliferation
Minutes Hours Days
The T cell activation cycle
IL-2 etc.
IL-2R
Effector functions:HelpDTHKilling (CTL)regulation
MHC class II/autopeptide
TCR
CD3
CD80
CD40
MHC class II
CD40CD40
CD40L
CD28 CD80
Activated T cell
(1) induction of cytokines/chemokines (IL-8, IL-12, TNF-, MIP-1)
(2) stimulation of CD80 and CD86 expression and co-stimulatory function with activation of T cell growth
(3) augmentation of antigen-presenting function
Key molecular interactions between T cells and APCs
Naïve CD4+ T cells differentiate into Th1 and Th2 subsets
Resting CD4+ cell
“pTh”
Activated CD4+ cell
IL-2 IL-2 IFN- TNF
IL-4 IL-5 IL-6 IL-10
IFN-, IL-12
IL-4, IL-13
IL-4 IL-10(–)
IFN-(–)
Th1 Cells
Th2 Cells
Antigen + APC
IL-2 IFN- TNF
IL-4 IL-5 IL-6 IL-10
IL-4 IL-10(–)
IFN-(–)
Th1 Cells
Th2 Cells
Functions of Th1 subsets• 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
• Help B cells and induce humoral immunity
• mediate allergic and immediate hypersensitivity responses
• involved in antibody mediated immune diseases like SLE and ITP
Functions of Th2 subsets
Functions of Th subsets
(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 Function- regulates the cell mediated and antibody responses
Major Functions of T Lymphocytes
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 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.
MHC Class llANTIGEN
Internalization of antigen/Ig
Antigenic peptidesBind to MHC class IImolecules
B cell
BCR(SmIg)
Peptide
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 Processing and Presentation by B cells
MHC class II/ carrier peptide complex
B cell
Antigen Presentation by B cells
BCR(SmIg)
hapten
carrier protein
carrier peptides
MHC class II
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.
Antigen
CD4
TCR
CD4
MHC class II
MHC class II
BCR(SmIg)
BCR(SmIg)
MHC class II
TCRIL-2R
CD40L
Expression of Membrane Proteins Following Antigen Specific Activation of T and B Cells
Resting B cell
Resting EffectorT cell
CD23
CD40
Activated B cell
ActivatedEffector
T cell
CD80CD86
Sm Ig
Activated B Cell
CD40 CD4
TCRCD40L
CD23
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
CONSEQUENCES OF CD40L/CD40 INTERACTIONS DURING T-B CELL INTERACTIONS
LymphokinesIL-2, IL-4, IL-5, IL-6, IFN-, TGF
IgGIgAIgE
Plasma Cell
Final Phases of B cell Differentiation are Mediated by Contact T cell signals (CD40L/CD40) and Lymphokines
SmIg
Activated B cellCD40
CD23
CD4
TCRCD40L
Activated Effector T cell
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.
The Hyper IgM Syndrome (HIM)
(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 Function- regulates the cell mediated and antibody responses
Major Functions of T Lymphocytes
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, IL-1 and IL-12 as well as chemotactic and migration inhibitory factors restricting granulocytes, macrophages and eosinophils to the site of inflammation.
Delayed Type Hypersensitivity (DTH)
DTH Pathway of Contact Hypersensitivity
CD4+ Th1 cell
APCActivated CD4+ Th1 cell
TCR
CD4
CD40L CD40
Macrophage/mesenchymal cell
Proinflammatory moleculesChemokines (IL-8, SDF-1)Lymphokines (IL-1, GM-CSF,TGFIFN, IL-12, IL-6NO, proteolytic enzymes, PGE2
CD40 dendritic cell
activateddendritic cell
Activated macrophages,mesenchymal cells andendothelial cells
Inflammation inducingCD40L/CD40 interactions
Th1 CD4+ T Cells Induce Inflammation and DTH
CD40L
CD3TCR
CD4
Fc receptor
IL-12 IL-1IL-6IL-12TNFTGF-
MHC class II
IFN-cytotoxic granules
IL-2Receptor
IL-2
MHC II
Macrophage
Activated MacrophageActivated Th1 Cell
T Cell- Macrophage Interactions
CD4 Th1 CellCD28 B7 (CD80)
CD40L
CD28
TCR
CD4
CD80
CD80
IL-12
EosinophilMast Cell
CD2
TCR
CD4
CD4
Macrophage/Dendritic cell
MHC II/peptide
Fc Receptor
Antigen/IgG
IL-1, TNF, IL-6
IL-3, IL-4, IL-5 IL-3, IL-8
fibroblasts endothelial cell
hypothalamus
fever
TCR
IL-2R
IL-2
granulocytes
IFN-
CD4+ TH1 T Cell
Phagocytosiskilling
Physiology of the DTH Response
IL-2 IFN- TNF
IL-4 IL-5 IL-6 IL-10
IL-4 IL-10(–)
IFN-(–)
Th1 Cells
Th2 Cells
Functions of Th1 subsets• 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
• Help B cells and induce humoral immunity
• mediate allergic and immediate hypersensitivity responses
• involved in antibody mediated immune diseases like SLE and ITP
Functions of Th2 subsets
Functions of Th subsets
