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Immunology. Apr 2011; 132(4): 540–548.
PMCID: PMC3075507

Interleukin-21 induces the differentiation of human Tc22 cells via phosphorylation of signal transducers and activators of transcription

Abstract

Interleukin-21 (IL-21) exerts critical functions in T helper type 17 (Th17) cell development. However, the effect of IL-21 on the differentiation of IL-22-producing T cells is not clear. Here we showed that IL-21 induced the differentiation of human naive CD8+ T cells into Tc22 cells without the expression of IL-17. The addition of transforming growth factor-β inhibited the production of IL-22 but induced the production of IL-17. Both IL-15 and IL-2 induced interferon-γ production but did not induce differentiation of Tc22, which suggests that common γ-chain signals are not specific to promote IL-22 synthesis. The IL-21 induced naive CD8+ T cells to produce IL-22 in greater amounts than memory CD8+ T cells. In addition, we demonstrated that IL-21 promoted the proliferation and increased the expression of IL-21 receptors on activated naive CD8+ T cells. Furthermore, IL-21 increased the expression of granzyme B molecules. Analysis of molecular mechanisms indicated that IL-21 induced phosphorylation of signal transducers and activators of transcription 1, 3 and 5 in CD8+ T cells. Overall, our data indicated that IL-21, an effector cytokine produced by CD4+ T cells, might mediate the cross-talk between CD4+ and CD8+ T cells through the production of IL-22.

Keywords: CD4/helper T cells, CD8/cytotoxic T cells, cytokine, interleukin-21, Tc22

Introduction

Interleukin 21 (IL-21) is a recently identified member of the common γ-chain (γc) -signalling family of cytokines that includes IL-2, IL-7 and IL-15.1 Interleukin-21 is an effector cytokine that is produced by various T helper cell subsets, including T follicular helper cells, T helper type 17 (Th17), Th2 and Th1 cells, and natural killer T cells.2,3

The functional IL-21 receptor consists of IL-21R and γc IL-21R is expressed on T cells, B cells, natural killer cells, dendritic cells, macrophages and epithelial cells, indicating roles of IL-21 in both innate and adaptive immune responses.4 Interleukin-21 signals via the janus kinase–signal transducers and activators of transcription (JAK-STAT) pathway. Depending on the cell type, IL-21 activates Janus family tyrosine kinases JAK1 and JAK3 to the activation of STAT1, STAT3, STAT4 and STAT5.4,5 Interleukin-21 potently stimulates the differentiation of B cells into antibody-forming cells. Moreover, IL-21 synergizes with IL-15 in proliferation and activation of both naive and memory CD8+ T cells.6 Most recently, IL-21 has been demonstrated to exert a critical function in Th17 development.2,3,7

Interleukin-22, a member of the IL-10 family, plays an important role in host defence, inflammation and tissue repair.810 It signals through a receptor complex, IL-22R1/IL-10R2.11 The IL-22R1 is expressed specifically on epithelial and some fibroblast cells in peripheral tissues such as gastrointestinal, respiratory system and skin but not on immune cells.12 Expression of IL-22 is augmented in many autoimmune diseases. The up-regulation of IL-22 is detected in Crohn's disease, ulcerative colitis, psoriatic skin and preclinical mouse inflammatory bowel disease models. Studies in the mouse Klebsiella pneumonia infection model and mouse Citrobacter rodentium infection model support the essential role of IL-22 in mucosal immunity for the control of various infections.9,10 Our previous study and other reports demonstrate that IL-22 may play a role in the defence against fungal infections such as Candida albicans.8,13 It may also play a role in tumour progression; it has been reported that IL-22 potentiated the expression of inducible nitric oxide synthase in human colon carcinoma cells.14

Our results showed that IL-21 induced human naive CD8+ T cells to differentiate into Tc22 cells via phosphorylation of STAT1, STAT3 and STAT5. Moreover, IL-21 promoted the proliferation and IL-21R expression of activated naive CD8+ T cells, which suggests a positive feedback loop in the amplification of the IL-22+ CD8+ T cells.

Materials and methods

Subjects

Umbilical cord blood was collected from healthy full-term newborn infants at the Secondary Affiliated Hospital of Sun Yat-sen University. Healthy volunteers between the ages of 20 and 26 years were recruited from Sun Yat-sen University. Adequate informed consent was obtained from all individuals involved in this study. The study was approved by the Medical School Review Board at Sun Yat-sen University, China.

Monoclonal antibodies

The following antibodies were used for cell surface and intracellular stainings as well as for cell culture: CD8-allophycocyanin (APC), CD4-FITC, CD4-peridinin chlorophyll protein (PerCP), interferon-γ (IFN-γ) -APC, IFN-γ-FITC, GranzymB-FITC, phosphor-STAT1-phycoerythrin (PE), phosphor-STAT3-PE, phosphor-STAT4-FITC, phosphor-STAT5-FITC, phosphor-STAT6-APC, isotype-matched control antibodies, purified anti-CD3 and anti-CD28 monoclonal antibodies were purchased from BD Bioscience PharMingen (San Jose, CA). The IL-17-PE was purchased from eBioscience (Santiago, Chile) and IL-22-APC, IL-22-PE and IL-21R-PE were purchased from R & D Systems (Minneapolis, MN).

Preparation of cord and peripheral blood mononuclear cells

We separated mononuclear cells from the cord blood of newborns as naive cells. For preparation of cord blood mononuclear cells (CBMCs), heparinized cord blood was mixed sufficiently with Dextran 500 solution (GE Healthcare Bio-Sciences, Uppsala, Sweden), and incubated at 37° in a 5% CO2 incubator for 30 min to remove erythrocytes. The CBMCs were obtained by Ficoll–Hypaque density gradient centrifugation.

We separated the mononuclear cells from peripheral blood of adults and then isolated CD8+ CD45RA+ T cells as naive CD8+ T cells and CD8+ CD45RO+ T cells as memory CD8+ T cells. Peripheral blood mononuclear cells (PBMCs) were isolated from blood using Ficoll–Hypaque density gradient centrifugation. Cells were resuspended at a concentration of 2 × 106/ml in complete RPMI-1640 medium (Gibco, Grand Island, NY) supplemented with 10% fetal calf serum (Sijiqing, China), 100 U/ml penicillin, 100 μg/ml streptomycin, 50 μm 2-mercaptoethanol and 2 mm l-glutamine (all from Gibco).

Isolation of T-cell subsets

Naive CD8+ T cells were isolated from CBMCs by positive selection with anti-CD8 microbeads (Miltenyi Biotec, Bergisch Gladbach, Germany). To purify naive and memory CD8+ T cells from PBMCs, CD8+ T cells were negatively isolated from PBMCs using a biotin–antibody cocktail (Miltenyi Biotec). Subsequently, purified CD8+ T cells were incubated with anti-CD45RA and anti-CD45RO microbeads (Miltenyi Biotec) respectively. CD8+ CD45RA+ and CD8+ CD45RO+ cells were obtained by positively selecting from the column. The purity of cells, assessed by flow cytometry (FACSCalibur; Becton Dickinson, San Jose, CA) exceeded 97% for each T subset. Cells were resuspended at a concentration of 0·5 × 106/ml in complete RPMI-1640 medium.

Cell culture conditions

The CBMCs were stimulated with soluble anti-CD3 (0·2 μg/ml) plus anti-CD28 (1 μg/ml) in the presence of various doses of IL-21 (Peprotech, Rocky Hill, NJ, USA) for 4 days. CD8+ CD45RA+ or CD8+ CD45RO+ T cells were stimulated with plate-bound anti-CD3 (1 μg/ml) plus anti-CD28 (1 μg/ml) in the presence or absence of IL-21 (50 ng/ml) or IL-15 (20 U/ml) for 4 days. Naive CD8+ T cells from CBMCs were stimulated with anti-CD3 plus anti-CD28 in the presence or absence of IL-21 (50 ng/ml), IL-15 (20 U/ml; Peprotech), IL-2 (50 U/ml; Peprotech) or IL-21 plus transforming growth factor-β (TGF-β; 1 ng/ml; Peprotech) for 4 days. Culture supernatants were collected for the assay of cytokines by ELISA. The cells were harvested and rested in the presence of IL-2 (10 U/ml) for 3 days and restimulated with PMA (20 ng/ml; Sigma-Aldrich, Saint Louis, MO, USA) + ionomycin (1 μg/ml; Sigma-Aldrich) and used for flow cytometry analysis or RNA extraction. Culture supernatants for 72 hr were used for cytokine measurement by ELISA.

CFSE labelling

Purified CD8+ T cells from CBMCs or CD8+ CD45RA+ T cells from PBMCs were resuspended in complete RPMI-1640 medium at 107 cells/ml. Carboxyfluorescein diacetate succinimidyl ester (CFSE; Invitrogen, Carlsbad, CA) was added at a final concentration of 5 μm, and the cells were incubated for 10 min at 37° in 5% CO2. The stain was quenched using five times the volume of ice-cold complete RPMI-1640 medium for 5 min. The cells were then washed three times and resuspended in complete RPMI-1640 medium.

Detection of phosphorylated STATs

The CBMCs were activated with anti-CD3 and anti-CD28 for 2 days, rested overnight, and then restimulated with or without IL-21 (50 ng/ml) for 15 min. The cells were then fixed in 2% formaldehyde, permeabilized in 90% methanol and labelled with anti-phospho-STAT1, -STAT3, -STAT4, -STAT5 or -STAT6 monoclonal antibody.

Cell surface and intracellular cytokine staining

To detect IL-21R expression, purified CD8+ T cells from CBMCs were stimulated with plate-bound anti-CD3 plus anti-CD28 in the presence or absence of IL-21 (50 ng/ml). On day 4, cells were harvested, washed and stained with anti-IL-21R for 30 min at 4°. After staining, cells were washed and resuspended in PBS. For intracellular cytokine production, CBMCs or purified CD8+ from CBMCs were stimulated and rested as described above, and restimulated with PMA + ionomycin for 5 hr in the presence of Brefeldin A (10 μg/ml; Sigma-Aldrich). Cells were then washed, fixed and permeabilized, at which time cytokines and granzyme B staining as well as isotype-matched control antibodies were added to the cells and incubated for 30 min at 4°. After intracellular staining, cells were washed and resuspended in PBS. Flow cytometry was performed using a BD FACS Calibur cytometer. Lymphocytes were gated on forward and side scatter profiles and analysed using FlowJo software (Treestar, San Carlos, CA).

Polymerase chain reaction

The CBMCs were stimulated and rested as described above, and restimulated with PMA + ionomycin. After 5 hr of stimulation, total RNA was extracted by TRIzol (Invitrogen) according to the manufacturer's instructions. Reverse transcription of total RNA was performed at 37° using the ReactionReady™ First Strand cDNA Synthesis kit (Invitrogen). Amplification of cDNA was conducted in a DNA thermal cycler (Biometra, Goettingen, Germany) at the following conditions: denaturation 45 seconds at 94°, annealing 45 seconds at 65° for glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and IL-22, followed by 1 min of elongation at 72°. Rounds of PCR were repeated for 35 cycles each for both GAPDH and IL-22. The following sense and antisense primers for each molecule were used: IL-22 sense, 5′-CTCTTGGCCCTCTTGGTACAG-3′; IL-22 antisense, 3′-CGCTCACTCATACTGACTCCG-5′; GAPDH sense, 5′-GCA TGG CCT TCC GTG TCC-3′; GAPDH antisense, 5′-TGA GTG TGG CAG GGA CTC-3′. The ratio of IL-22 over GAPDH was calculated according to the relative intensities of the bands revealed under UV illumination with Bio-1D software (Vilber Lourmat, Marne la Vallee, France).

ELISA

Cell-free culture supernatants were harvested and assayed by ELISA for IL-22 (R & D Systems), IL-17 (eBioscience) and IFN-γ (BD Bioscience PharMingen) production according to the manufacturer's protocols, respectively.

Statistical analysis

Data are presented as the mean ± SD values. Comparison between two groups was performed by unpaired or paired Student's t-tests. A value of P < 0·05 was considered significant.

Results

IL-21 induces the differentiation of human Tc22 cells

To examine whether IL-21 has any effect on the development of IL-22-producing T cells in humans, we stimulated CBMCs with anti-CD3 plus anti-CD28 in the absence or presence of IL-21. The results showed that anti-CD3 plus anti-CD28 induced a low level of IL-22 mRNA expression by CBMCs. Interleukin-21 markedly increased the transcription of IL-22 mRNA (Fig. 1a). In addition, anti-CD3 plus anti-CD28 could not induce IL-22 or IL-17 production at protein level. The IL-21 enhanced production of IL-22 and IFN-γ in a dose-dependent manner but did not increase the production of IL-17 (Fig. 1b). Flow cytometric analysis revealed that IL-21 enhanced IL-22 expression both in CD4+ and CD8+ T cells, whereas the frequency of IL-22-producing cells in CD8+ T cells was much higher than in CD4+ T cells (Fig. 1c,d).

Figure 1
Interleukin-21 (IL-21) induces the expression of IL-22 at mRNA and protein level in cord blood mononuclear cells (CBMCs). (a) CBMCs were primed with anti-CD3 and anti-CD28 in the absence or presence of IL-21, rested and restimulated with PMA and ionomycin. ...

To determine whether IL-21 could induce the differentiation of Tc22 cells, we purified CD8+ T cells from CBMCs and cultured cells with anti-CD3 plus anti-CD28 in the presence or absence of IL-21 (primary stimulation), then rested and restimulated cells with PMA plus ionomycin (secondary stimulation). In the primary stimulation, anti-CD3 plus anti-CD28 could not induce IL-22 production, addition of IL-21 markedly promoted IL-22 production. Anti-CD3 plus anti-CD28 induced IFN-γ production and IL-21 significantly enhanced IFN-γ secretion (Fig. 2a). In the secondary stimulation, anti-CD3 plus anti-CD28 induced CD8+ T cells to produce a low level of IL-22 and IFN-γ. The IL-21-treated CD8+ T cells secreted significantly more IL-22 and IFN-γ than IL-21-untreated CD8+ T cells (Fig. 2a). In addition, the frequency of IL-22+ and IFN-γ+ CD8+ T cells was significantly higher in IL-21-treated CD8+ T cells than in CD8+ T cells without IL-21 treatment. Interleukin-21 alone had no effect on the IL-17 production from CD8+ T cells. Further analysis indicated that approximately 60% of CD8+ IL-22+ cells did not express IFN-γ with IL-21 stimulation (Fig. 2b,c). Taken together, these results demonstrate that IL-21 induces the differentiation of human Tc22 cells without IL-17 production.

Figure 2
Interleukin-21 (IL-21) induces the differentiation of Tc22 cells. (a) Purified CD8+ T cells from cord blood mononuclear cells (CBMCs) were primed with anti-CD3 and anti-CD28 in the absence or presence of IL-21 (primary stimulation), rested and restimulated ...

IL-21 but not IL-15 or IL-2 induces the differentiation of naive CD8+ T cells into Tc22 cells

Interleukin-21 belongs to the common γc cytokine family and displays structural similarities and functional overlaps with IL-15 and IL-2. We further investigate whether IL-15 and IL-2 have similar effects on the production of IL-22. The results showed that IL-15 and IL-2 did not increase IL-22 expression. Moreover, all of the cytokines tested significantly promoted IFN-γ production (Fig. 3a). These results indicate that the common γc cytokines have distinct effects on IL-22 production.

Figure 3
Interleukin-21 (IL-21) but not IL-15 or IL-2 induces the differentiation of Tc22 cells. (a) Purified naive CD8+ T cells were stimulated with anti-CD3 and anti-CD28 with or without the indicated cytokines. The levels of IL-22 and interferon-γ (IFN-γ) ...

It has been reported that TGF-β inhibited IL-22 production in CD4+ T cells and was a critical factor in the development of Th17 cells.3 To investigate the effect of TGF-β on the production of IL-22 by CD8+ T cells, we stimulated naive CD8+ T cells with anti-CD3 and anti-CD28 in the presence or absence of IL-21 plus TGF-β. The results showed that the addition of TGF-β inhibited the production of IL-22 but induced the production of IL-17 (Fig. 3b,c).

To further determine IL-22 production by naive and memory CD8+ T cells, we purified subsets of naive (CD45RA+) and memory (CD45RO+) CD8+ T cells from PBMCs and stimulated the two populations with anti-CD3 plus anti-CD28 in the presence or absence of IL-21 or IL-15. Interleukin-21 induced a large amount of IL-22 production by activated naive CD8+ T cells (Fig. 3d left graph). Anti-CD3 plus anti-CD28 induced a low level of IL-22 and addition of IL-21 slightly increased IL-22 production by memory CD8+ T cells (Fig. 3d right graph). Naive CD8+ T cells produced IL-22 in greater amounts than memory CD8+ T cells with IL-21 stimulation. In addition, IL-15 had no effect on IL-22 production in naive CD8+ T cells but could induce IL-22 production by memory CD8+ T cells.

IL-21 induces the division of activated naive CD8+ T cells

Purified naive CD8+ T cells were labelled with CFSE and stimulated with anti-CD3 and anti-CD28 in the presence or absence of IL-21 for the indicated times. Cells were then collected for flow cytometric analysis for cell division. On day 3, both CD8+ T cells from CBMCs and CD8+ CD45RA+ T cells from PBMCs treated with IL-21 had more divisions than those cells without IL-21 treatment. On day 6, the proliferation of IL-21-treated CD8+ T cells was markedly higher than non-stimulated and anti-CD3 plus anti-CD28-stimulated cells (Fig. 4a). In addition, on day 3, the cell number of CD8+ T cells from CBMCs was threefold to fourfold higher in culture with IL-21 than in culture with anti-CD3 and anti-CD28 alone (Fig. 4b).

Figure 4
Interleukin-21 (IL-21) induces the division of activated naive CD8+ T cells. (a) Kinetics of division. Purified CD8+ T cells from cord blood mononuclear cells (CBMCs) or purified CD8+ CD45RA+ T cells from peripheral blood mononuclear cells (PBMCs) were ...

IL-21 increases IL-21R and granzyme B expression

Purified CD8+ T cells from CBMCs were cultured with anti-CD3 and anti-CD28 in the presence or absence of IL-21, and the expression of IL-21R was assessed by flow cytometry. The results showed that IL-21R was expressed at a low level on resting naive CD8+ T cells. Interleukin-21 up-regulated the expression of IL-21R following stimulation with anti-CD3 plus anti-CD28 (Fig. 5a). Moreover, stimulation of CD8+ T cells with anti-CD3 plus anti-CD28 resulted in higher levels of mean fluorescence intensity (MFI) of IL-21R expression than untreated cells (P < 0·05). Addition of IL-21 further increased the MFI of IL-21R (Fig. 5a).

Figure 5
Interleukin-21 (IL-21) increases IL-21R and granzyme B expression. (a) Purified CD8+ T cells from cord blood mononuclear cells (CBMCs) were stimulated with anti-CD3 and anti-CD28 in the absence or presence of IL-21. The expression and the mean fluorescent ...

We further examine the expression of granzyme B in IL-21-treated naive CD8+ T cells. The results showed that a low frequency of CD8+ T cells expressed granzyme B following anti-CD3 and anti-CD28 stimulation. Addition of IL-21 markedly enhanced granzyme B expression and IL-22+ CD8+ T cells produced granzyme B simultaneously (Fig. 5b). These findings indicate that both IL-22+ CD8+ and IL-22 CD8+ T cells contribute to the cytolytic function.

IL-21 mediates induction of IL-22 via the phosphorylation of STATs

Signalling through the IL-21R/γc may involve different JAK/STAT molecules in different responding cells. We therefore examined the phosphorylation of STATs in human naive CD8+ T cells following IL-21 stimulation. Stimulation of CD8+ T cells with IL-21 resulted in phosphorylation of STAT1 in more than 60% of cells and more than 30% of CD8+ T cells expressed phosphor-STAT3 and phosphor-STAT5. However, phosphor-STAT4 and phosphor-STAT6 were detected at low levels (Fig. 6). Therefore, IL-21 may achieve its effect by activating target genes downstream of STAT1, STAT3 and STAT5 in the activated naive CD8+ T cells.

Figure 6
Induction of phosphorylation of signal transducer and activator of transcription (STAT) proteins in activated CD8+ T cells following interleukin-21 (IL-21) stimulation. The cord blood mononuclear cells were activated with anti-CD3 and anti-CD28 for 2 ...

Discussion

Interleukin-21 is a pleiotropic cytokine that has a broad range of activations on immune cells. The effect of IL-21 on the differentiation of Th subsets is beginning to be delineated. In vitro stimulation of naive CD4+ T cells under Th1- or Th2-polarized conditions showed no differences in the levels of IFN-γ or IL-4 in normal and IL-21R knockout mice,15 suggesting that IL-21 has no effects on the differentiation of Th1 and Th2 cells in mice. However, IL-17 production was significantly lower in CD4+ T cells from IL-21R knockout mice than in those from normal mice under Th17-polarized conditions, demonstrating that IL-21 exerts critical functions in Th17 cell development.3,7 Two recent papers have described an IL-22-producing helper T cell population that co-expresses the chemokine receptor CCR6 and the skin-homing receptors CCR4 and CCR10.16,17 These cells are distinct from both Th17 cells and Th1 cells. However, the effect of IL-21 on the differentiation of IL-22-producing T cells is not clear.

It has been shown that IL-21 up-regulates the expression of IL-22 mRNA in activated naive CD4+ T cells.3 Consistent with these results, we found that IL-21 induced IL-22 production in activated naive CD4+ T cells at protein level. Unexpectedly, we demonstrated that IL-21 also induced IL-22 production in activated naive CD8+ T cells and the frequency of IL-22-producing cells in CD8+ T cells was higher than in CD4+ T cells from CBMCs. Moreover, IL-21 did not induce IL-17 production in CD8+ T cells. These data suggest that there are some differences between the induction of IL-22 and IL-17. A transcription factor that might be involved in IL-22 expression is the aryl hydrocarbon receptor. The aryl hydrocarbon receptor agonist substantially alters the balance of IL-22 versus IL-17-producing cells.16 In line with previous studies showing that TGF-β, the critical factor in the development of Th17 cells, inhibited IL-22 production in CD4+ T cells,3 we showed that the addition of TGF-β inhibited the production of IL-22 but induced IL-17 production in activated naive CD8+ T cells.

Our results demonstrated that, compared with IL-23 (data not shown), IL-21 induced higher levels of IL-22 in activated naive CD8+ T cells. Interleukin-21 belongs to the common γc-signalling cytokine family that includes IL-2, IL-7 and IL-15. Here, we found that IL-21 but not IL-15 or IL-2 induced the differentiation of Tc22 cells by naive CD8+ T cells, clearly indicating that signals mediated by the common γc are not specific to enhance IL-22 production. We found that IL-21 induced IL-22 production in naive and memory CD8+ T cells. However, naive CD8+ T cells stimulated with IL-21 produced IL-22 production in greater folds than memory CD8+ T cells.

In vivo experiments demonstrated that IL-21 by itself had little effect on naive CD8+ T-cell proliferation and expansion.6 Our results showed that IL-21 enhanced naive CD8+ T-cell proliferation in the presence of T-cell receptor signals. Granzyme B plays an important role in cytotoxicity. Our data showed that most of the IL-22+ and IL-22 CD8+ T cells expressed granzyme B following stimulation of IL-21. Furthermore, both percentage and intensity of IL-21R on CD8+ T cells increased following stimulation with IL-21, which suggests that IL-21 may be part of a positive feedback loop to amplify the frequency of IL-22+ CD8+ T cells.

Based on the cell types, IL-21 activates different STATs signals. It has been reported that IL-21 stimulation of primary splenic B cells induces activation of STAT5 and IL-21 induces the activation of STAT1, STAT3 and STAT4 but not STAT5 in human natural killer cells. We here showed that IL-21-induced IL-22 production in human CD8+ T cells was dependent on the activation of STAT1, -3, -5.

One recent study has demonstrated that CD161+/++ CD8+ T-cell populations in PBMCs from healthy individuals secreted high levels of IL-22.18 Another report demonstrated that approximately 20% of CD8+ T cells produced IL-22 in atopic dermatitis lesions and there was a strong correlation between the frequency of CD8+ IL-22+ T cells and the atopic dermatitis disease severity index.19 We estimate that the IL-22+ CD8+ T cells might play a role in the pathogenesis of some diseases. Interleukin-21, an effector cytokine produced by CD4+ T cells, might mediate the cross-talk between CD4+ and CD8+ T cells through the production of IL-22.

Acknowledgments

This study was supported by a grant from the National Key Basic Research Program of China (973; No. 2007CB512404), Yat-sen training programme of innovative talent (50000-3126200) and National Natural Science Foundation of China (81072403).

Glossary

Abbreviations

APC
allophycocyanin
CBMCs
cord blood mononuclear cells
CFSE
carboxyfluorescein succinimidyl ester
GAPDH
glyceraldehyde 3-phosphate dehydrogenase
IFN
interferon
IL-21
interleukin-21
JAK
Janus kinase
PBMC
peripheral blood mononuclear cells
PE
phycoerythrin
PerCP
peridinin chlorophyll protein
STAT
signal transducer and activator of transcription
TGF
transforming growth factor
Th17
T helper type 17

Disclosures

The authors declare no competing financial interests.

References

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