Role of Costimulation in Immune Response 2003. 4. 9.

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Role of Costimulation in Immune Response2003.
4. 9.

• Yong-Hoon Chung, MD, PhD
• Department of Microbiology
• Hanyang Univ College of Medicine

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Central Tolerance vs Peripheral Tolerance
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Costimulation of antigen and co-receptor activated
T cells
SIGNAL 1
Antigen Recognition
Antigen-receptor and co-receptor ligation are
often insufficient for proliferation and the
expression of effector function
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Co-stimulation of T helper cells by professional
APC
CD28
Signal 1 signal 2 are required for T cell
clonal proliferation and differentiation to
effector cells
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Mechanism of co-stimulation in T cells
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Costimulatory molecules also associate with
inhibitory receptors
Cross-linking of CD28 by B7 co-stimulates and
induces CTLA-4
CTLA-4 binds CD28 with a higher affinity than B7
molecules to shut down the T cell response.
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Co-stimulation in the induction of T cell anergy
SIGNAL 1 ONLY
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Fig. 1. PD-LPD-1 and other B7CD28 family
members. The structures, interactions and
functions of five of each of B7 ligand and CD28
family members are depicted schematically. aa
indicates the number of amino acid residues of
the cytoplasmic tail. Y represents a tyrosine
residue. and - indicate costimulatory and
coinhibitory signaling, respectively. Molecular
weights are those of the glucosylated form. CD28,
CTLA-4 ICOS are homodimers. ind, inductive M,
monocyte APC,antigen-presenting cell EC,
extracellular doman.
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Table 1. The B7 family of costimulatory ligands
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Fig. 2. Role of NKG2D engagement in human and
mouse NK cells. (a) Ignorance normal cells are
spared from NK cell cytolytic activity, by
signals (-) from MHC I specific inhibitory
receptors(inh NKR, dark blue). Inhibitory NKR
include CD158 (KIR-L) CD85j(LIR1/ILT2) in
humans, inhibitory Ly49 in mice CD94NKG2A
heterodimers in both species. In no stress, most
cells dont express ligands for NKG2D same for
ligands of NCR. Activating signals can be
mediated, beside NCR, also by activating NKR
these are not shown but include activating
CD158(KIR-S) in humans, Ly49D, Ly49H and Ly49P in
mice and CD94NKG2C heterodimers in both species.
(b) Tolerance upon distress, cells may express
only low levels of NKG2D ligands (NKG2D-L, light
green), ligands of NCR (NCR-L, light red)
ligands for activating NKR(not shown). In these
conditions, the inhibitory signal (-) initiated
by engagement of inhibitory NKR overcomes
activation signals (). (c) Elimination this can
be mediated (i) via costimulation or (ii) after
primary recognition'. (i) Cellular distress
inhibit MHC I expression upregulation of
NKG2D-L also NCR-L(ligands of activating NKR).
These modifications allow NK activation via
NKG2D NCR(NKR), which cooperate to overcome
inhibitory signals mediated by NKR. (ii) Stressed
cells expressing low levels of NCR-L (ligands of
activating NKR), but hi levels of NKG2D-L, are
eliminated by NK cells solely via NKG2D
engagement.
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Importance of ICOSB7RP-1 costimulation in acute
and chronic allograft rejectionÖzkaynak, E. et
al. Nature Immunology 2, 591 - 596 (2001)
Figure 2. Blockade of ICOSB7RP-1 costimulation
inhibits acute allograft rejection. (a) The
anti-ICOS mAb 12A8 did not deplete ICOS T cells,
as shown by flow cytometric analysis of
splenocytes 24 h after intraperitonal injection
of mAb (200 g). Staining of splenocytes with a
secondary (2) antibody alone (mouse antirat
IgG2b) detected anti-ICOS bound to CD3 splenic T
cells in treated, but not control, mice.
Additional mAb increased T cell staining only
marginally (upper right panel) and untreated mice
had similar numbers of ICOS T cells (lower right
panel) as animals receiving anti-ICOS therapy.
(b) Northern analysis compared expression of ICOS
and B7RP-1 RNA in control hearts versus cardiac
allografts collected at day 7 after transplant
from recipients treated with IgG or a blocking
anti-ICOS (mAb 12A8). A murine GAPDH cDNA
fragment was used as a control for loading (data
are representative of three grafts per group).
Beginning at the time of engraftment, wild-type
(ICOS/) allograft recipients were treated daily
for 14 days with (c) anti-ICOS or (d) ICOS-Ig
fusion protein and monitored daily to determine
the effects of therapy on allograft survival.
Allograft survival in ICOS-/- recipients was also
prolonged. Survival data are mean s.d. and are
representative of six animals per group. Plt0.005
compared to other groups, as determined using
Mann-Whitney U test
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In vivo stimulation of CD137 broadens primary
antiviral CD8 T cell responses Halstead, E. S.
et al. Nature Immunology 3, 536 - 541 (2002)
Figure 4. Effects of in vivo CD137 stimulation on
the immunodominant NP(366374) CD8 T cell
response in CD28-/- mice. Pulmonary lymphocytes
were collected 10 days after intranasal infection
with influenza virus and were stained with CD8
mAb and DbNP(366374) tetramers. (a)
Representative flow cytometry plots are shown.
Numbers indicate the percentages of CD8 T cells
that stained positive for the NP(366374)
tetramer. Pooled data from five independent
experiments (n 12 in each group) show cells
that stained positive for CD8 and NP(366374)
tetramer as a measure of (b) total CD8 T cells
(c) total lymphocytes and (d) the absolute
numbers of NP(366374)-specific CD8 T cells. (e)
Representative experiment showing cytotoxicity of
pulmonary lymphocytes against NP(366374)
peptideloaded target cells.
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Signaling through OX40 (CD134) breaks peripheral
T-cell tolerancePratima Bansal-Pakala et al.
Nature Medicine 7, 907 - 912 (2001)
Figure 2 OX40 signals, provided at the time of
soluble antigen exposure, promote T-cell
expansion and prevent induction of
hypo-responsiveness. Recipients of V3/V11 CD4 T
cells were tolerized with soluble peptide and
treated with anti-OX40. a, Accumulation of V3/V11
CD4 cells after 10 d in mice injected with PBS
alone (bottom), or soluble peptide and either
control IgG (middle) or anti-OX40 (top) given on
day 2. Values represent means of 3 individual
mice per group s.e.m. b, Accumulation of V3/V11
CD4 cells after 17 d with mice challenged on day
10 with peptide in CFA. Mice initially injected
with PBS (second bottom), or soluble peptide and
either control IgG (second top) or anti-OX40
(top) given on day 2. Controls receiving PBS with
no peptide/CFA challenge (bottom). Values
represent means of 3 individual mice per group
s.e.m. c and d, Proliferation (c) and IL-2
production (d) per V3/V11 CD4 T cell after
restimulation in vitro with peptide on day 17.
Comparison between T cells from mice challenged
on day 10, after initial injection with PBS alone
() versus soluble peptide and either control IgG
() or anti-OX40 (). IL-2 values are from pooled
triplicate cultures. Similar results were seen in
2 separate experiments.
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Inhibition of natural killer cells results in
acceptance of cardiac allografts in CD28-/-
mice Stefan Maier et al.
Nature Medicine 7, 557 - 562 (2001)
Figure 5 Depletion of NK-receptorbearing cells
leads to prolonged survival of allogeneic cardiac
grafts in CD28-/- recipients. a, Number of
circulating DX5CD3- NK cells in anti-NK1.1 or
control-treated recipients. The percentage of NK
cells was monitored in peripheral blood on day -4
(prior to antibody treatment) and on days 1 and 4
after treatment. b, Allograft survival in
anti-NK1.1treated H-2b, CD28-/- recipients (),
anti-NK1.1treated H-2b, CD28/ recipients ()
and control-treated H-2b, CD28-/- recipients ()
after transplantation of allogeneic (BALB/c,
H-2d) cardiac grafts. c, Histological analysis of
explanted allogeneic cardiac grafts after
transplantation (as in Fig. 1b). Explantation of
cardiac grafts was at day 5
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Cellular Expression of costimulatory molecules
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Positive/Negative Role of costimulatory molecules