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T Lymphocytes in Skin Lesions of Psoriasis and Mycosis Fungoides
Express B7-1: A Ligand for CD28
By Brian J. Nickoloff, Frank 0. Nestle, Xiang-Guang Zheng, and Laurence A. Turka
The activation of T cells requires t w o distinct signals. One
signal involves interaction of the antigen-specific T-cell receptor with major histocompatibility complex molecules
plus antigenic peptide; a second signal, which is antigen
nonspecific, is the interaction of CD28 with its natural ligands B7-1 and B7-2lB70. CD28 is expressed on 80% of T
cells, is upregulated after activation, and binds t o B7 genefamily members, found onantigen-presenting cells. Because
maligof ourinterest in the immunologicbasis of benign and
nant T-cell-mediated disorders of the skin, we investigated
the cellular distribution of CD28 and B7 family members in
lesions of psoriasisand mycosis fungoides. By immunostaining cryostat sections of skin, CD28 was found t o be expressed on virtually all lymphocytes in the epidermis and
dermis of both skin diseases. Surprisingly, 87-1 was also
found t o b e expressed on virtually all lymphocytes in the
epidermis and dermis ofboth skin diseases. B7-1expression
was confirmed on CD3+T lymphocytes usingflow cytometry
of single cell suspensions of fresh, unfixed psoriatic lesional
tissue. To exclude the possibility that this
result wascaused
by a second reagent contaminating the monoclonal antibody (MoAb) preparation, t w o different lots were used, and
the MoAb was
absorbed onto Chinese hamster ovary (CHO)
transfectants expressing 87-1, or vector-onlytransfected
CH0 cells. Theseprocedures confirmed that a 87-1-like epitope was being recognized on psoriatic lesional T cells. In
contrast t o 87-1 expression on lymphocytes, B7-3, as defined
by anti-BB-l MoAb reactivity, was found primarily on epidermalkeratinocytes in both skin diseases andwas not
found onT cells. These results indicatethat within t w o common skin disorders, lesional T cells accumulate in the dermis
and epidermis, which express B7-1. Such expression may
permit self-costimulation involving theCD28-mediated activation pathway, and thereby contribute to the
ongoing T-cell
proliferation present in these chronic, benign, and malignant
skin diseases.
6 1994 by The American Society of Hematology.
A
dermal compartments in psoriatic lesions, as well as in cutaneous lesions obtained from patients with cutaneous T-cell
lymphoma (mycosis fungoides). Immunostaining of the majority of skin-seeking T cells was unexpected because B7- l
has been reported not to be expressed by circulating PB T
cells; although it can be upregulatedonblood-derived
Tcells after activation in vitro.”’.“ When this MoAb was preabsorbed by incubating with Chinese hamster ovary (CHO)
cells transfected with a full-length B7-1 cDNA, all staining
was abolished, thusindicating that this result was not caused
by a second reagent contaminating the MoAb preparation.
but that the anti-B7-lMoAbwasalso
binding to the T
cells. These data indicate that T-cell expression of B7- I can
occur during T-cell activation in vivo, at sites of cutaneous
inflammation or neoplasia.
CTIVATION OF RESTING T lymphocytes usually requires at least two distinct signals. The first signal is
interaction of the antigen-specific T-cell receptor(TCR) with
class I1 major histocompatibility complex (MHC) molecules
and antigenic peptides; whereas the second signal involves
antigen-nonspecific “costimulation,” generally delivered by
antigen-presenting cells(APCs) ofhematopoietic origin.’
Several molecules have been proposed to provide this costimulatorysignal,thebestcharacterized
of whichisthe
CD28 molecule expressed on T cells. Several related CD28ligands, B7-I, B7-24370, andB7-3/BB-I havebeen
described, and are found onAPCs.”‘ Our recent demonstration
that the majority of T cells in psoriatic lesions express CD28
was not ~urprising,~
because 60% to 80% of peripheral blood
(PB) T cells express CD28.’ It is also known that during Tcell activation CD28 expression is increased.’ When psoriatic lesions were further investigated using several different
monoclonal antibodies (MoAbs). it was observed that keratinocytesstainedwith
anti-BB-lMoAbs(now
known to
bind to B7-3/BB-I), but not with anti-B7-1 M o A l ~ s . ~
As a follow-upto thesestudies, we recently immunostained skin samples using a commercially available MoAb
against B7-1. We were surprised to observe that this MoAb
stained the vast majority of T cells in both epidermal and
From the Departments of Puthology und Medicine, Universin of
Michigun Medical School, Ann Arbor, MI.
Submitted September 22, 1993; accepted December 27. 1993.
Supported by National Institutes of Health Grants No. AR40065.
AR01823, AR40488 ( B J . N ) ; IPO AR41703 (L.A.T)
Address reprint requests toLaurence A. Turka, MD, PhD, Univers i q of Michigan, 1560 MSRB-11, 1150 W Medical Center Dr. Ann
Arbor, MI 48109-0676.
The publication costs of this article were defruyedin part by page
charge p u y e n t . Thisarticle musf theretbrebe hereb.y marked
“advertisement” 111 uccordunce with I8 U.S.C. section 1734 solely to
indicate this ,fuct.
0 1994 by The American Sociee of Hematology.
0006-497//94/8~09-0019$3.00/0
2580
MATERIALS AND METHODS
Clinicul sumples. Punchbiopsies ( 3 mm)wereobtained
from
tive untreated psoriatic plaques and four untreated plaques of mycoa different
sisfungoides.Each
biopsy samplewasderivedfrom
patient after obtaining informed consent. PB samples were obtained
by venipuncture and collected in EDTA-containing syringes from
normalhealthyadultvolunteers.Mononuclearcellswereisolated
from the Ficoll-Hypaque interface after centrifugation. Highly puntied resting T cells were further enriched from these interface cells
by vigorous negative selection using a cocktail of MoAbs against B
cells, monocytes, natural killer cells, and activated (ie,
HLA-DR’)
T cells,together with magneticbeads as previouslydescribed.”
These T cells were greater than 98% CD3+, lacked HLA-DR. and
IO
did not proliferate in response to phytohemagglutinin A (PHA,
pg/mL). Dermal mononuclear cells were also obtained from psoriatic
lesions by keratome sampling of untreated lesions and isolating lymphocytes and dendritic cells as previously described.’’ Briefly, the
epidermis is separated from dermis using dispase, and the dermal
fragmentsmincedandplacedinculturemedium(RPMI
1640 +
10% fetal calf serum [FCS]; GIBCO, Grand Island,NY) for 2 days.
After this incubation period, mononuclear cells are isolated from the
loosely attached dermal fragments and surrounding suspension
by
centrifugation. After resuspending the pellet in RPMI + 10% FCS.
these cells include primarily
T lymphocytes and dermal dendritic
cells which can be distinguished by their forward- and side-scatter
Blood, Vol 83,No 9 (May l ) , 1994: pp 2580-2586
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2581
T CELLS COEXPRESS CD28 AND 87-1 IN SKIN
100
L
a,
Ll
E
3
Z
0
100
10'
102
103
Fluorescence Intensity
Fig l. Validation of binding capacity of anti-67-1 MoAb L307.4.
Fresh 87-l-transfected CH0 cells were stained with the anti-67-1
MoAb U07.4 (-1,
with isotype-matched control MoAb (. . '1, or
with W07.4 MoAb which had been serially absorbed l4 cycles) on
67-1 CH0 cells before staining as outlined in Materials and Methods
l- -1. Vectorsnly-transfected CH0 cells h o t shown) exhibited a
staining profile indistinguishable from background.
-
+
properties using a flow cytometer (see below). All cells were maintained in a humidified incubator with 5% CO2 at 37°C.
MoAbs. The primary antibodies used included MoAbs against
B7-1 (clone L307.4 Becton Dickinson Advanced Cellular Biology,
San Jose, CA), B7-3BB-1 (anti-BB-l, obtained as a gift from Peter
Linsley, Bristol Myers Squibb Pharmaceutical Corp, Seattle, WA),
and CD28 (Becton Dickinson). Anti-HLA-DR MoAb (L243) was
obtained through the America Type Culture Center (Rockville, MD).
Isotype control antibodies included preparations of either IgG or
IgM antibodies (Coulter Corp, Hialeah, FL). All antibodies were
used at a final concentration of 10 pg/mL.
fmrnunoabsorption studies. To verify that the MoAb against B71, L307.4, recognized the B7-1 antigen, C H 0 cells transfected with
a full-length B7-1 cDNA (gift of P. Linsley) were stained. The B71 transfectants, butnotvector-onlytransfected
cells werestrongly
positive using the MoAb L307.4. Moreover, serial absorption of the
anti-B7 MoAb by the CHO-B7-I transfected cells showed proportional decreases after repetitive cycles of coincubation, until there was
essentially no significant immunoreactivity of the anti-B7-l MoAb
using fresh CHO-B7-1 transfected cells (see Fig 1). The immunoabsorption was performed by sequentially mixing 1 mL of the anti-B71 (IO pg/mL) with lo7 CHO-B7-l transfected cells, or vector-only
transfected CH0 cells, for 1 hour. After this coincubation, the cells
were pelleted and the MoAb in the Supernatant reexposed to a fresh
batch of transfected cells, and the process repeated a total of four
times.
Flow cytometry analysis. Between 5 X IO4 to 5 X lo5 T cells
were stained with a primary MoAb, and these primary MoAbs detected using fluorescein isothiocyanate (FITC)-conjugated goat-antimouse IgG (Tago Inc, Burlingame, CA). For the transfected CHOB7-1 cells, they were used at IO6 cells/mL and stained in a two-step
procedure in thesamemanner as the T lymphocytes. For doublelabeling experiments, directly conjugated (phycoerythrin [PE]-labeled)
primary MoAb against CD3 was used together with the appropriate
blocking steps in connection with the indirect immunofluorescence
staining as above for B7-1. Flow cytometric analysis was performed
using a FACScan equipped with Lysis 2 software (Becton Dickinson,
Mountainview, CA).
Imrnunostaining procedure. Five-micron thick cryostat sections
of skin were immunostained using a sensitive avidin-biotin immunoperoxidase technique (Vectastain Kit, Vector Labs, Burlingame,
CA), with 3-amino-4-ethyl carbazole as the chromogen producing a
positive-red-reactive product as previously described.' For doublelabeling experiments a directly conjugated (PE-labeled) primary
MoAb against CD28 was used together with appropriate blocking
steps in conjunction with anti-B7-1 MoAb and FITC-conjugated
goat-antimouse IgG as described above. An Olympus BH-2 fluorescence microscope equipped with both red and green filters was used
to visualize the positively stained cell types.
T-cell activation. Polyclonal proliferation of resting PB T cells
was induced using immobilized anti-CD3 MoAb (G19-4; gift of J.
Ledbetter, Bristol Myers Squibb Pharmaceutical Corp) and IL-2 (100
U/mL; Boehringer-Mannheim, Indianapolis, IN) for 12 days in
RPM1 1640 plus 10% FCS as previously described.'" For these
experiments, 96-well round-bottom microtiter plates were coated
with anti-CD3 MoAb as previously described? PB T cells before
and after the stimulation were analyzed for HLA-DR expression and
B7-1 expression by flow cytometry with the indicated reagents.
RESULTS
Immunostaining of cryostat sections of skin lesions for
B7-I, CD28, and B7-3/BB-I. Because of the unexpected
immunoreactivity of the lymphocytes with the B7 MoAb
L307.4 as described below, we carefully tested the antigenic
recognition capability of this MoAb. The object of this testingwas to verify that the commercially obtained MoAb,
L307.4, bound to the B7-1 molecule, and that the preparation
was not contaminated with a second antibody that was reacting with the T cells. The anti-B7-l MoAb strongly reactedwith CHO-B7-l transfected cells, butnot controltransfected, B7-1 -negative C H 0 cells (Fig I). Additionally,
upon serial testing of the MoAb after sequential exposure
to CHO-B7-1+ cells, flow cytometry showed that by four
absorption cycles, the staining intensity of fresh CHO-B7I positive cells was reduced to below isotype control, background levels (Fig 1). Similar staining was observed for both
lots of MoAb, L307.4, and the staining intensity diminished
as the MoAb concentration was reduced from 10 pg/mL to
1 ,ug/mL; and was nonexistent at concentrations below 1 pg/
mL. Thus, we concluded that the MoAb was indeed recognizing an epitope exposed on the B7-1 molecule.
Immunostaining cryostat skin sections using this anti-B7l MoAb showed that virtually all ofthe round lymphoid cells
in both the epidermis and dermis of psoriatic and mycosis
fungoides lesions were positive (Fig 2). This staining pattern
was observed for all biopsy specimens, and a representative
example is shown in Figure 2A, which is a psoriatic plaque
stained with anti-B7-1. Note the strong and diffuse staining
of the round lymphoid cells in both epidermal and dermal
compartments (Fig 2B). The determination that these indicated cells are actually lymphocytes is based ontheir staining
in serial sections for CD3 and either CD4 or CD8 (data not
shown). The prominent accumulation of CD3+ T cells, but
not B lymphocytes, in psoriatic plaques has been previously
documented by several group^.'^ Staining of serial sections
also showed that greater than 95% of the CD3+ cells in the
psoriatic plaque were also CD28' as previously described'
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NICKOLOFF ET AL
2582
C
Fig 2
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T CELLSCOEXPRESSCD28
AND B7-1 IN SKIN
2583
Fig 3. (A) Mycosis fungoides plaque
with diffuse and intensepositive 87-1 immunoreactivity on enlarged round lymphocytes in both
dermis and epidermis.Note the large positively stained Pautrier microabscess. (B) Mycosis fungoides plaque with diffuse and intense
positive CD28 immunoreactivity on lymphocytes in dermis and epidermis including the Pautrier microabcess. (C) Mycosis fungoides
plaque stainedfor BB-l shows strong and diffusestaining of epidermal keratinocytes, but no positive staining of lymphocytes.
Fig 2. (page2582) (A) Psoriatic plaque with diffuse and intense
positive 87-1 immunoreactivity on round lymphoid cells. (B) Within
a psoriatic plaque, 87-1 positive lymphoid cells are present in both
epidermal and dermal compartments. (C) Psoriatic plaque stained
with anti-B7-1 plus FITC-conjugated goat-antimouse antibody, followed by phycoerythrin-conjugatedanti-CD28 antibody. Upper panel
viewed through a fluorescein filter shows numerous positive round
a dendritic epidermal Langerhans
lymphoid cells (curved arrow), and
cell (straight arrow). The latter was identified by characteristic dendritic morphology best observedwhen focusing up anddown on the
field. The lower panel is the same field examined using the rhodamine filter and shows that allthe B7-1+lymphoid cells are also CD28+
(curved arrow). (D) Psoriatic plaque stained for BB-l shows strong
and diffuse staining of keratinocytesin both the
basal and suprabasal
portion of the epidermis. No staining of the lymphoid cells in either
epidermis or dermiswere observed.
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2584
NICKOLOFF ET AL
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(data not shown). A double-stained cryostat section examined by fluorescence microscopy confirmed coexpression of
B7-1 on the CD28+ T lymphocytes (Fig 2C). When the
CHO-B7-1 absorbed MoAb preparation was used, all immunoreactivity on the lymphocytes was abolished (data not
shown). The ability of B7-l-absorption to abrogate T-cell
immunoreactivity shows that the same antibody is binding
both to recombinant B7-1 and to the T cell.
The keratinocytes, endothelial cells, and dermal dendritic
cells were B7-1-. An occasional epidermal Langerhans cell
was B7-1+, as previous de~cribed.~
Staining the psoriatic
lesions for B7-3BB-1 with anti-BB-l MoAb showed positive staining of basal and suprabasilar keratinocytes, but no
staining of lymphoid cells (Fig 2D).
Figure 3A shows the B7-1 staining pattern of a representative mycosis fungoides lesion. Note the strong and diffuse
staining of the lymphoid cells (identified as T cells by staining of serial sections with CD3, CD4, and CD8-data not
shown) in both the dermis and epidermis including a large
Pautrier microabscess. Staining of serial sections showed
that the infiltrating lymphocytes diffusely expressed CD28
in both dermal and epidermal compartments, including the
large Pautrier microabscess present in the epidermis (Fig
3B). When the CHO-B7 absorbed MoAb preparation was
used, all immunoreactivity on the lymphocytes was abolished (data not shown). Staining mycosis fungoides lesions
for B7-3BB-l showed strong positivity in the epidermis
(particularly basal layer keratinocytes), but no staining of
lymphocytes was observed (Fig 3C).
Flow cytometric analysis ofpsoriatic lesional Tcells. TO
verify that the immunoreactivity for B7-1 on the T cells in
theseskin biopsies wasnot caused byafixation artifact,
lesional T cells were directly obtained from fresh unfixed
'4
Fig 4. Flow cytometric analysis of psoriatic le
sional T aells shows podtive CD3 expression
B7and
1 coexpreuion. (A) shows the forward- and side
scatter propmti- of the & m a l 4 1 s llymphocvta
are present in the -8 d d m a t e d Rl). IC1 shows
CD3 positivity (y axial of these lymphwith
negative isotypacontrolstaining (x axis).(B) shows
that all CD3+ cells (y axis) are B7-1+ (x axis). (D)
shows that the 87-1 immunoreactivity is abolished
(x axis) if the anti-B7-1 M o b is preab.0rb.d with
B7-1+CH0 cells, whereas the CD3 immunoreactivity
ly axis)
is
unaffected.
keratome samples, and subjected to two-color immunofluorescence analysis by flow cytometry. The T cells could be
separated from dermal dendritic cells by their forward and
side-scatter properties (Fig 4A). The exact nature of the
round lymphoid cells was confirmed by their CD3 expression
(Fig 4C). These CD3' T cells were also positive for B7-1
using the MoAb L307.4 (Fig 4B). Using the CHO-B7-l
absorbed antibody, this B7-1 immunoreactivity was abolished (Fig 4D). For the representative experiment shown in
Fig 4, the mean fluorescent intensity on lesional T cells for
the control MoAb was 2.4, and for B7-1 it was 26.7, yielding
a B7-1:control ratio of 11: 1.Thus, specific B7-1 staining on
lesional T cells was greater than l log above background.
Flow cytometric analysis of PB T cells. RestingPBT
cells were HLA-DR- (data not shown), but expressed a low
level of B7-1 that was consistently seen as only a slight shift
of the fluorescence intensityover isotype control staining(Fig
SA). For example in Fig 5A, the mean fluorescent intensity
on lesional T cells for the control MoAb was 19.6, and for
B7-1 it was 61.6, yielding a B7-1:control
ratio of only 3:l.
Thus the amount of specific B7-l staining on PB T cells was
significantlylessthan the values of 10 times above background seen for T cells isolated from psoriatic lesions (Fig
4). After CHO-B7-1 absorption, this B7-1 immunoreactivity
was diminished to near background levels. There was no increase in B7-1 expression observed whenT cells were stimulated for 12 days on tissueculture plates coated with immobilized anti-CD3MoAb (Fig SB-mean fluorescent intensities:
control MoAb = 18.0, B7-1 = 44.2, ratio = 2.5:1), despite
induction of HLA-DR expression on these cells and visible
activation with blastogenesis and
cluster formation as seen by
phase-contrast microscopy (data not shown).
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T CELLSCOEXPRESS
A
CD28 AND 87-1
2585
IN SKIN
lo01
100
10'
102
103
Fluorescence Intensity
102
103
Fluorescence Intensity
Fig 5. Staining ofPB T cells withanti-67-1 MoAb. (A) Highly
purified resting T cells were isolated from PB and stained with anti87-1 MoAbI-),
with isotype-matchedcontrol MoAb l....), or with
anti-B7-l MoAb that had been serially absorbed (4 cycles) on B7-lt
CH0 cells before staining as outlined in Materials and Methods
(-1. (B) Highly purified restingT cells were stimulated with immobilized anti-CD3 MoAb (619-4) for12days, removed, and stained
with anti-B7-l MoAb or with isotype-matchedcontrol MoAb.
-
DISCUSSION
This report documents that virtually all lymphocytes in
the dermis and epidermis of a benign (ie, psoriasis) and
malignant (ie, mycosis fungoides) T-cell-mediated skin disease express B7-1, a CD28 ligand. These T cells also coexpress CD28 raising the interesting possibility of autocrine
costimulation via B7-1:CD28 interaction. The antibody we
used to identify B7-1, L307.4, was raised against B7-1transfected cells (L. Lanier, personal communication, No-
vember 1993), and is specific for B7-1; although the exact
epitope on the B7-1 molecule that it recognizes has not been
precisely identified. Nonetheless, we believe the MoAb is
indeed recognizing a specific site on B7-1 based on the
considerations above and on our own results absorbing the
MoAb against CHO-B7-1+ cells.
Compared with PB T cells that only weakly express B71, the psoriatic and mycosis fungoides dermal T cells were
more strongly B7-lf. Based on our current results, it appears
that once the PB T cells enter the skin, there is accumulation
of a subset that is expressing B7-1. At least two possible
explanations for these results can be suggested: (1) local
activation of a B7-1- T-cell population of a population that,
initially, only weakly expresses B7-1, or (2) selective recruitment from the blood of an extremely low frequency (<1%
of total T cells), and currently undetectable, subset of
strongly B7-1+ T cells. With respect to the first possibility,
because our in vitro stimulation experiments did not upregulate B7-1 on PB T cells, there may be other activation pathways for induction of B7-1 operative in vivo in these two
skin diseases that are not being simulated by our in vitro
protocol. Thus, based on the available data, we cannot definitely confirmeither of the two aforementioned possibilities.
It should be mentioned that using this MoAb against B71, our results dealing with PB T cells have some similarities
as well as differences with previous reports using different
MoAbs against B7-1."." In contrast to these previous reports, we observed a low level of B7-I expression on resting
PB T cells. However, after 12 days of stimulation no further
increase was observed, which is in agreement with Sansom
and Hall," but in disagreement with Azuma et al." Sansom
and Hall required more than 30 days of stimulation before
detection of B7-1 on PB T cells. We followed the stimulation
protocol exactly as described by Azuma et al, and our only
explanation for these differences is that the MoAbs used to
detect B7-1 were different amongst each study. The finding
of B7- 1 on T cells in these two persistent dermatoses in vivo
may reflect the fact that such lesional T cells have undergone
chronic stimulation over several months.
Another important finding relates to the discordant expression of B7-1 versus B7-3/BB-1 on the T cells and keratinocytes. In the past, B7-1 andB7-3/BB-1 were thought to
be identical antigens (termed B7/BB-1). However, we first
described a discordant pattern of expression on activated
keratinocytes in vitro and in vivo,' and the finding that these
are distinct epitopes has since been confirmed by others.6
These current findings further confirm and extend the conclusion that B7 and BB-l are not identical antigens because
the T cells express B7-1, but not B7-3BB-1; whereas the
keratinocytes express B7-3BB- I , but not B7-1 immunoreactivity. It should be noted that the anti-B7-3/BB-I MoAb
has cross-reactivity with B7-1 under certain circumstances,
such as expression of the B7- 1 gene in C H 0 cells. However,
in our tissue sections (figures 2D and3C) and in flow cytometry7 (data not shown), anti-B7-3/BB-1 MoAb stains keratinocytes but not T cells. It may not be possible to determine
the cause of this phenomenon until the B7-3/BB-1 gene is
further identified and/or cloned. However, it does suggest
that reactivity with the anti-B7-3/BB-l MoAb might recognize a posttranslational modification of a protein product,
From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
2586
NICKOLOFF ET AL
one which might not be made in T cells. Immunoprecipitation-based studies as well as efforts to clone the B7-3BB1 gene are underway to definitively establish the identity of
B7-3BB-1 and to permit direct comparison with the B7-1
gene product.
In conclusion, these results indicate that B7-1 (but not
B7-3BB-1) is expressed by lymphocytes in two common
and chronic skin disorders; one benign (psoriasis) and one
malignant (mycosis fungoides). These lymphocytes also express CD28, and such cell-surface expression would theoretically permit a T cell to be able to undergo self-costimulation
via interaction with B7-1. Such participation of costimulatory molecules may contribute to the ongoing T-cell proliferation that occurs in the skin of patients afflicted by these
disorders.
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I 1 . Sansom DM, Hall ND: B7BB1, the ligand for CD28, is
expressed on repeatedly activated human T cells in vitro. Eur J
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From www.bloodjournal.org by guest on June 15, 2017. For personal use only.
1994 83: 2580-2586
T lymphocytes in skin lesions of psoriasis and mycosis fungoides
express B7-1: a ligand for CD28
BJ Nickoloff, FO Nestle, XG Zheng and LA Turka
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