CD57 Expression and Cytokine Production by T Cells in
Lesional and Unaffected Skin from Patients with
Mariana D. Batista1,2*, Camilla Tincati1, Jeffrey M. Milush1, Emily L. Ho1¤a, Lishomwa C. Ndhlovu1¤b,
Vanessa A. York1, Esper G. Kallas2,3, Jorge Kalil2,3, Sheila M. Keating4,5, Philip J. Norris4,5,6, David Chang7,
Patrick Unemori8, Kieron S. Leslie8, Toby Maurer8, Wilson Liao8, Douglas F. Nixon1
1Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America, 2Division of
Clinical Immunology and Allergy, School of Medicine, University of Sa ˜o Paulo, Sa ˜o Paulo, Brazil, 3Instituto de Investigac ¸a ˜o em Imunologia, University of Sa ˜o Paulo, Sa ˜o
Paulo, Brazil, 4Blood Systems Research Institute, San Francisco, California, United States of America, 5Department of Laboratory Medicine, University of California San
Francisco, San Francisco, California, United States of America, 6Department of Medicine, University of California San Francisco, San Francisco, California, United States of
America, 7California Pacific Medical Center - Davies Campus, San Francisco, California, United States of America, 8Department of Dermatology, University of California
San Francisco, San Francisco, California, United States of America
Background: The immunopathogenic mechanisms leading to psoriasis remain unresolved. CD57 is a marker of replicative
inability and immunosenescence on CD8+ T cells and the proportion of CD57 expressing CD8+ T cells is increased in a
number of inflammatory conditions.
Methodology: We examined the expression of CD57 on T cells in the skin of patients affected with psoriasis, comparing
lesional and unaffected skin. We also assessed functionality of the T cells by evaluating the secretion of several inflammatory
cytokines (IL-17A, IFN-gamma, IL-2, IL-33, TNF-alpha, IL-21, IL-22, and IL-27), from cell-sorted purified CD4+ and CD8+ T cells
isolated from lesional and unaffected skin biopsies of psoriasis patients.
Principal Findings: We observed that the frequency of CD57+CD4+ and CD57+CD8+ T cells was significantly higher in
unaffected skin of psoriasis patients compared to lesional skin. Sorted CD4+ T cells from psoriatic lesional skin produced
higher levels of IL-17A, IL-22, and IFN-gamma compared to unaffected skin, while sorted CD8+ T cells from lesional skin
produced higher levels of IL-17, IL-22, IFN-gamma, TNF-alpha, and IL-2 compared to unaffected skin.
Conclusions/Significance: These findings suggest that T cells in unaffected skin from psoriasis patients exhibit a phenotype
compatible with replicative inability. As they have a lower replicative capacity, CD57+ T cells are less frequent in lesional
tissue due to the high cellular turnover.
Citation: Batista MD, Tincati C, Milush JM, Ho EL, Ndhlovu LC, et al. (2013) CD57 Expression and Cytokine Production by T Cells in Lesional and Unaffected Skin
from Patients with Psoriasis. PLoS ONE 8(2): e52144. doi:10.1371/journal.pone.0052144
Editor: Luzia Helena Carvalho, Centro de Pesquisa Rene Rachou/Fundac ¸a ˜o Oswaldo Cruz (Fiocruz-Minas), Brazil
Received July 31, 2012; Accepted November 8, 2012; Published February 28, 2013
Copyright: ? 2013 Batista et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported in part by the National Institutes of Health (grants AI64520), Fundac ¸a ˜o de Amparo a Pesquisa do Estado de Sa ˜o Paulo (04/
15856-9/Kallas and 2010/05845-0/Kallas and Nixon), and the Peter and Shelagh Godsoe Family Foundation. DN was supported in part by UCSF REAC grant
no. 37710/521717. ELH was a recipient of the American Academy of Neurology Clinical Research Training Fellowship. JMM was supported in part by the National
Institutes of Health (grant 5T32HL007185). WL was supported in part by grants from the National Institute of Musculoskeletal and Skin Diseases (5K08AR057763)
and the International AIDS Society in collaboration with the NIH-funded Centers for AIDS Research, U.S. National Institutes of Health, and the UW Institute of
Translational Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: Esper Kallas and Douglas Nixon are PLOS ONE Editorial Board members. This does not alter the authors’ adherence to all the PLOS ONE
policies on sharing data and materials.
* E-mail: email@example.com
¤a Current address: Department of Neurology, University of Washington, Seattle, Washington, United States of America
¤b Current address: Hawaii Center for AIDS, Department of Tropical Medicine, University of Hawaii, John A. Burns School Medicine, Honolulu, Hawaii, United
States of America
Psoriasis is an inflammatory skin disease where immunologic
imbalance and altered keratinocyte differentiation lead to
hyperproliferation of the skin . Although psoriasis was initially
classified as a Th-1-polarized disease, a clear role for CD4+ T cells
that produce IL-17A and IL-22 (Th-17 and Th-22 cells) has been
established in recent years, primarily at lesional sites, but also in
the blood [2,3,4]. The inflammatory milieu is the key determinant
for plaque development and maintenance, and each cell type
involved in the process has its own characteristic signature
cytokines. In psoriasis, IFN-gamma, the prototype Th-1 cytokine,
interplays with IL-2, TNF-alpha, IL-17, and IL-22 to contribute to
inflammation and altered differentiation [2,5,6].
PLOS ONE | www.plosone.org1February 2013 | Volume 8 | Issue 2 | e52144
Much debate exists regarding the relative contribution of CD8+
T cells to cytokine production in psoriasis, as CD8+ T cells may
also produce IL-17 and IL-22 [7,8]. CD57 is a marker of
replicative inability on T cells. CD57+CD8+ T cells expand in a
number of conditions of chronic immune activation, such as viral
infections , inflammatory diseases, including rheumatoid
arthritis and Wegener granulomatosis [10,11], and malignancies
. CD57+CD8+ T cells can also be expanded after physical
stress  and in aging . Although these cells exhibit limited
proliferative and survival abilities, they nonetheless manifest high
cytotoxic properties, being destined to migrate to non-lymphoid
tissues without further cycling [12,15,16]. We sought to investigate
the role of CD57 expression on T cells in lesional and non-lesional
unaffected skin of psoriasis patients.
Twenty patients with psoriasis were included in this study, 11
males and 9 females. Severity was distributed as follows: mild
(n=10), moderate (n=6), and severe (n=4). The median age was
51 years (inter-quartile range 38–56 years). The most common
predisposing factors listed were stress, skin injury, and lack of sun
exposure during winter.
Increased CD57 expression on CD4+ and CD8+ T cells in
unaffected skin of psoriatic patients
We first determined whether the CD4+ or CD8+ T cell
distribution was altered in unaffected skin compared to lesional
skin of psoriasis patients. CD45+ leukocytes in skin samples
(psoriatic lesions and non-lesional) were assessed by flow cytom-
etry. We observed a significantly higher percentage of CD4+ T
cells in lesional skin compared to unaffected skin (Figure 1A).
Although there was a trend towards higher percentages of CD8+
T cells in lesional skin, the difference was not significant
To determine whether T cells were terminally differentiated, we
examined the frequency of CD57+ T cells in the skin (Figure 2A
and B). Interestingly, the frequency of CD57+CD4+ and
CD57+CD8+ T cells was significantly higher in unaffected skin
of psoriasis patients compared to lesional skin (Figures 2A and 2B).
CD57 expression in skin was not correlated with the subject’s age
(data not shown).
Sorted CD4+ and CD8+ T cells from lesional skin produce
higher levels of cytokines than unaffected skin
Several cytokines have been known to play in role in psoriasis,
however the secretion at different sites and the cell type producing
them remains unknown. We therefore performed a selected
cytokines Multiplex assay to measure key inflammatory mediators
IL-17A, IFN-gamma, IL-2, IL-33, TNF-alpha, IL-21, IL-22, and
While unstimulated samples from all compartments did not
seem to produce significant cytokine levels, we observed that
lesional skin CD4+ T cells stimulated with PMA-ionomycin
produced higher levels of IL-17A, IL-22, and IFN-gamma in
relation to unaffected skin from the same patients (Figure 3). There
was a trend to higher production of TNF-alpha and IL-2 by sorted
CD4+ T cells from lesional skin, while no difference was observed
for IL-27 levels (Figure 3).
For CD8+ T cells, we observed that the production of IL-17A,
IL-22, IFN-gamma, TNF-alpha, and IL-2 were higher in lesional
skin than unaffected skin of psoriasis patients (Figure 4).
Despite the fact that IL-21 and IL-33 have been implicated in
psoriasis pathogenesis [17,18,19], we could not find any difference
in the production of these cytokines between lesional and
unaffected skin of psoriasis patients (data not shown).
IL-22 levels produced by CD4+ T cells were correlated to
We next assessed whether the levels of IL-17A or IL-22
produced by lesional skin CD4+ or CD8+ T cells were correlated
to the other cytokines that were tested. Only the levels of IL-22
produced by CD4+ T cells isolated from lesional skin were
correlated to TNF-alpha, IFN-gamma, and IL-2 (Figure 5). No
other associations were found.
CD57 expression on CD8+ T cells determines lack of
proliferation ability, associated with short telomeres, defining
replicative senescence that occurs in conditions of chronic immune
activation, such as HIV-1 infection . CD57+CD8+ T cells
exhibit up-regulated expression of cytotoxicity genes, such as
perforin, granulolysin, and granzyme B, indicating increased
cytotoxic ability, and a higher IFN-gamma and TNF-alpha
production upon TCR stimulation [15,20]. On CD4+ T cells,
CD57 expression has also been associated with decreased
proliferation capacity, and affects CD4+ T cell function, being
associated with higher IFN-gamma but lower IL-2 production
Figure 1. T cell distribution in skin and PBMC of psoriasis
patients. Frequency of (A) CD4+T cells and (B) CD8+T cells in the skin
(lesional and unaffected) from psoriasis patients (n=7). *=p,0.05.
CD57 Expression on T Cells in Psoriasis
PLOS ONE | www.plosone.org2February 2013 | Volume 8 | Issue 2 | e52144
. Whether CD57+CD4+ and CD57+CD8+ T cells can
contribute to psoriasis immunopathogenesis remains poorly
understood. One previous study has demonstrated by immuno-
histochemistry the presence of CD57+ cells in psoriasis patients,
showing higher numbers in involved epidermis and papillary
dermis compared to uninvolved skin, while in reticular dermis,
uninvolved skin exhibited higher numbers of CD57+ cells
compared to normal control skin .
CD57+CD8+ T cells exhibit a phenotype compatible with
increased ability to migrate to tissues without further cycling .
They express higher levels of CX3CR1 than CD572CD8+ T
cells, which can dictate their migration to tissues . Interest-
ingly, 2 polymorphisms in the CX3CR1 gene were found to be
associated with psoriasis . One of these was a coding
polymorphism with higher frequency in healthy controls com-
pared to cases that is thought to impair the ability of CX3CR1 to
adhere to its ligand CX3CL1 . These genetic data support the
notion that recruitment of CD57+ lymphocytes into the skin via
the CX3CR1-CX3CL1 axis may be important in the pathogenesis
In this study, we found higher CD57 expression on CD4+ and
CD8+ T cells in unaffected skin of psoriasis patients compared to
lesional skin. In recent years, much attention has been given to non-
lesional unaffected skin of psoriasis patients, where quiescent auto-
reactive T cells named skin-resident T cells havebeen demonstrated
. CD57 is a marker of chronic antigenic stimulation. We could
hypothesize that some of the quiescent T cells present in non-
lesional sites express CD57 as a result of previous antigenic
stimulation. We do not know whether the site of unaffected skin
biopsy has previously been a lesional site. The persistence of a
population of CD8+ T cells in the dermis of resolved psoriasis
lesions after treatment has been demonstrated, and points to the
possibility of lesional memory [25,26]. Alternatively, as CD57
expression on T cells is associated with a decreased replicative
capacity, the high cellular turnover at lesional sites could result in
the lower survival of CD57+ T cells, leading to the finding of lower
CD57 expression in psoriasis lesions.
Unlike atopic dermatitis, where clear differences have been
shown between unaffected skin and normal skin from healthy
controls, in psoriasis unaffected skin has been considered largely
similar to normal skin . However, differences in gene
expression between uninvolved psoriasis skin and normal control
skin have also been shown . We have found higher CD57
expression in unaffected psoriasis skin compared to lesional skin.
CD57 expression on T cells has not been described in normal
control skin. We believe that the finding of higher CD57
expression is specific to uninvolved psoriasis skin, and is not a
consequence of similarities between uninvolved psoriasis skin and
normal control skin.
Figure 2. CD57 expression on T cells of psoriasis patients. CD57
expression on (A) CD4+T cells and (B) CD8+T cells from the skin of
psoriasis patients (n=7). *=p,0.05.
Figure 3. Sorted CD4+ + T cell cytokine production. Cytokine production by sorted CD4+ T cells from unaffected and lesional skin from psoriasis
patients, with stimulation with PMA-ionomycin. Comparative chart representing IL-17A, IL-22, IL-2, IFN-gamma, TNF-alpha and IL-27. *=p,0.05.
CD57 Expression on T Cells in Psoriasis
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Th-17 cells constitute a subset of CD4+ T cells that have the
distinct characteristics of being stimulated by IL-23, and produc-
ing IL-17A . IL-17A has been implicated as an important
cytokine in the pathogenesis of psoriasis. IL-17 mRNA levels are
higher in lesional skin in psoriasis than in normal skin from healthy
controls [3,30]. The presence of IL-17A in lesional tissue leads to
the release of multiple inflammatory cytokines by keratinocytes,
including TNF-alpha, IL-1, and IL-6 [3,31]. IL-17A can also
induce angiogenesis and the production of antibacterial peptides
. In addition, IL-17A induces keratinocyte expression of
chemokine genes that lead to neutrophil migration, thus contrib-
uting to overall inflammation . That is in contrast with the
effects of IFN-gamma, which induces preferential expression of
CXCL9, CXCL10, and CXCL11, that bind to activated T cells
containing CXCR3 .
IL-22, another important cytokine for psoriasis pathogenesis,
can be produced by CD4+ T and CD8+ T cells [8,33]. IL-22
through the Stat3 cascade and has the capacity of inducing
keratinocyte proliferation through the down-regulation of kerati-
nocyte differentiation genes, such as keratin 1 and fillagrin [34,35].
IL-22 induces anti-microbial proteins such as beta-defensins and
IL-22 mRNA expression is increased in psoriasis lesions compared
to normal skin [36,37].
In this study, we were able to compare the relative production of
IL-17 and IL-22, as well as IFN-gamma, IL-2, TNF-alpha, and
IL-27, in lesional and unaffected skin on the same individuals. We
found that CD4+ and CD8+ T cells isolated from lesional skin
have a higher ability to produce IL-17A than their counterparts
isolated from unaffected skin. We could hypothesize that T cells in
lesional skin have acquired the ability to secrete this cytokine due
to the local inflammatory environment or locally expressed
antigens. IL-22 production by CD4+ T cells isolated from lesional
skin was also higher than unaffected skin. They could correspond
to Th-17 cells or Th-22 cells. We could also demonstrate IL-22
production by sorted CD8+ T cells from lesional skin in low
amounts, in higher levels than unaffected skin. Interestingly, IL-22
production by CD4+ T cells isolated from lesional skin correlated
with TNF-alpha, IFN-gamma, and IL-2. CD8+ T cells isolated
from lesional skin exhibited a mixed cytokine profile between Th-
17 and Th-1, as higher production of IFN-gamma, TNF-alpha,
and IL-2 was also observed in lesional skin.
and proliferative pathways
In conclusion, we were able to assess phenotypic characteristics
and cytokine production by CD4+ and CD8+ T cells from lesional
and unaffected skin from the same patients. We demonstrated that
there are phenotypic and functional differences in T cells in
different sites in the same individuals. Further studies are needed
to elucidate the importance of unaffected tissue in psoriasis.
Materials and Methods
Twenty psoriasis patients were recruited for this study. Patients
provided informed consent and the study was approved by the
UCSF Institutional Review Board, according to the declaration of
Helsinki. Disease ranged from mild to severe and most patients
had a long history of psoriasis (median 12 years). Severity was
assessed based on affected body surface area (BSA), as follows:
mild - less than 5% BSA, moderate - 5–30% BSA, severe - more
than 30% BSA. Subjects included in the study were recruited
during their first visit to the Dermatology Clinic at San Francisco
General Hospital, and had not used topical or systemic therapy at
least 2 months prior to sample collection.
Patients were divided into 2 groups. For the phenotypic portion
of the study, 7 psoriasis patients were included. For the functional
part of the study (cell sorting and cytokine production), 13 patients
were included. Lesional and unaffected skin samples were
available for all patients. One patient was excluded from the
study due to low post-sorting purity levels.
Skin sample preparation
Skin samples were collected as 4-mm punch biopsies, one from
an active psoriatic lesion and another from unaffected skin, at least
5 cm away from an active lesion. The samples were incubated for
15 minutes at 37uC and then overnight at 4uC in 1 mg/ml
collagenase/dispase (Roche Diagnostics, Indianapolis, IN, USA)
and 10 units/ml recombinant DNAse I (Roche Diagnostics,
Indianapolis, IN, USA). Epidermis and dermis were both cultured
separately for 48 hours at 37uC in RPMI-1640 supplemented with
10% pooled human serum (Gemini Bio Products, Sacramento,
CA, USA), 1% penicillin and streptomycin, and 1 mol/L HEPES
buffer (Invitrogen, Carlsbad, CA, USA) in 6-well culture plates.
Single cell suspensions were obtained after rinsing through a
70 mm cell strainer (BD, San Jose, CA, USA), and cells isolated
Figure 4. Sorted CD8+ + T cell cytokine production. Cytokine production by sorted CD8+ T cells from unaffected and lesional skin from psoriasis
patients, with stimulation with PMA-ionomycin. Comparative chart representing IL-17A, IL-22, IL-2, IFN-gamma, TNF-alpha and IL-27. *=p,0.05,
CD57 Expression on T Cells in Psoriasis
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from epidermis and dermis were subsequently combined to
produce sufficient cell numbers for the subsequent experiments.
A multi-parameter flow cytometry analysis was performed using
an LSR II flow cytometer (BD Biosciences). Cells were first Fc
receptor blocked using 10 mg/ml human IgG (Sigma Aldrich, S.
Louis, MI, USA) for 20 minutes on ice. Cells were then stained for
30 minutes on ice with fluorophore-labeled antibodies, washed
with FACS buffer, and fixed with 2% paraformaldehyde
(Touisimis, Rockville, MD) in PBS. The data files were analyzed
using FlowJo Software version 8.8.6 (Tree Star, San Carlos, CA,
USA). The gating strategy is demonstrated in Figure S1.
CD4+ and CD8+ T cell sorting
Cells were stained using fluorescein isothiocyanate (FITC)-
conjugated anti-CD45 (eBioscience, San Diego, CA, USA),
phycoerythrin-Texas Red (ECD)-conjugated anti-CD3 (Beckman
Coulter, Brea, CA, USA), Alexa700-conjugated anti-CD4 (BD
Biosciences, San Jose, CA, USA), allophycocyanin-Cy7 (APC-Cy7)-
conjugated anti-CD8 (Biolegend,SanDiego,CA,USA), and Amine
Aqua (AARD) for live/dead discrimination (Invitrogen, Carlsbad,
CA, USA). Freshly isolated PBMCs and skin cells were incubated
withfluorochrome-conjugated antibodies and AARD antibodies for
30 minutes on ice. Cells were then washed twice with FACS buffer,
and sorted on a FACS Aria flow cytometer (BD Biosciences, San
Jose, CA, USA). During the first experiment (n=6), only CD8+ T
cells were sorted, using a doublet discrimination gating followed by
gating on CD45+ cells and CD3+CD8+ T cells. On the second
experiment (n=7), CD4+ and CD8+ T cells were sorted using a
doublet discrimination gating followed by gating on CD45+ cells
and finally on CD3+CD4+ and CD3+CD8+ T cells. The purities of
all sorts were greater than 95%. One patient was excluded due to a
75% post-sorting purity level.
T cell cultures
Sorted CD4+ and CD8+ T cells isolated from lesional and
unaffected skin and PBMCs from psoriatic patients were cultured
for 8 hours at 37uC and 5% CO2with or without PMA (50 ng/
ml) and ionomycin (500 ng/ml) stimulation (Sigma-Aldrich, St.
Louis, MO, USA) in a 96-well U-bottom plate. The plate was
centrifuged, the culture supernatant carefully removed, the cells
were washed with PBS, and fresh culture media containing IL-2
without PMA and ionomycin was added. The cells were then
placed back in culture at 37uC and 5% CO2for 7 days. On day 7
the plate was centrifuged and cell-free supernatants were frozen at
220uC for subsequent use in Luminex analyses.
Production of IL-17A, IFN-gamma, IL-2, IL-33, TNF-alpha,
IL-21, IL-22 and IL-27 were assayed using Multiplex cytokine
arrays (Biolegend, San Diego, CA, USA) following the manufac-
turer’s protocols. Samples were acquired on a Labscan 200
analyzer (Luminex, Austin, TX, USA) using Bio-Plex manager 6.0
software (Bio-Rad, Hercules, CA, USA). It should be noted that
the media for T-cell culture contained IL-2, so the comparative
analyses between groups are possible, though the analyte
concentrations obtained reflect the IL-2 added in the media.
The statistical analyses were performed using Prism Software
version 4.0a (GraphPad, La Jolla, CA, USA). Groups were
compared using the Wilcoxon paired non-parametric test with a
minimum significance value of p=0.05.
Gating strategy representing lesional skin sample.
We thank Terrence Ho for help with FACS sorting.
Recruited patients and obtained samples for analyses: MB PU KL TM DC
WL. Conceived and designed the experiments: JM EH LN EK JK DN.
Performed the experiments: MB CT VY SK PN. Analyzed the data: MB
JM LN WL EK DN. Contributed reagents/materials/analysis tools: SK
PN DC PU KL TM. Wrote the paper: MB JM EH LN EK JK WL DN.
Figure 5. IL-22 levels correlate to other cytokines. Correlation of
IL-22 levels produced by lesional skin CD4+ T cell with (A) TNF-alpha (B)
IFN-gamma (C) IL-2.
CD57 Expression on T Cells in Psoriasis
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CD57 Expression on T Cells in Psoriasis
PLOS ONE | www.plosone.org6 February 2013 | Volume 8 | Issue 2 | e52144