Newly characterized decidual Tim-3+ Treg cells are abundant during early pregnancy and driven by IL-27 coordinately with Gal-9 from trophoblasts

Abstract STUDY QUESTION What is the mechanism of Tim-3+ regulatory T (Treg)-cell accumulation in the decidua during early pregnancy and is its disruption associated with recurrent pregnancy loss (RPL)? SUMMARY ANSWER IL-27 and Gal-9 secreted by trophoblasts activate the Tim-3 signaling pathway in CD4+ T cells and Treg cells and so promote accumulation of Tim-3+ Treg cells, the abnormal expression of IL-27 and Gal-9 is associated with impaired immunologic tolerance in RPL patients. WHAT IS KNOWN ALREADY Tim-3+ Treg cells are better suppressors of Teff cell proliferation, and display higher proliferative activity than Tim-3− Treg cells. Tim-3+ Treg cells are tissue-specific promoters of T-cell dysfunction in many tumors. These cells express a unique factor that influences and shapes the tumor microenvironment. STUDY DESIGN, SIZE, DURATION The animal study included 80 normal pregnant mice. In human study, decidua tissues in the first trimester for flow cytometry analysis were collected from 32 normal pregnant women and 23 RPL patients. Placenta tissues for immunohistochemistry analysis were collected from 15 normal pregnant women. Placenta tissues for western blot analysis were collected from 5 normal pregnant women, 5 RPL patients and 5 women who have experienced one miscarriage. Blood samples for in vitro experiments were collected from 30 normal pregnant women. This study was performed between January 2017 and March 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS In this study, we investigated the kinetics of Tim-3+ CD4+ T-cell accumulation, and the proportions of Tim-3+ Treg cells throughout murine pregnancies using flow cytometry. We compared Tim-3 expression on decidual CD4+ T cells and Treg cells during normal pregnancies with expression on the same cell populations in women suffering from RPL. IL-27 and Gal-9 transcription and protein expression in the placenta were determined by RT-PCR and western blot, respectively. An in vitro co-culture model consisting of peripheral CD4+ T cells and primary trophoblasts from early pregnancy was used to mimic the maternal–fetal environment. MAIN RESULTS AND THE ROLE OF CHANCE The percentage of Tim-3+ Treg cells present in mouse uteri fluctuates as gestation proceeds but does not change in the spleen. Levels of Tim3+ Treg cells in uteri peaked at pregnancy Day 6.5 (E 6.5), then progressively diminished, and fell to non-pregnant levels by E18.5. In pregnant mice, Tim-3+ Treg cells constituted 40–70% of Treg cells in uteri but were present at much lower abundance in spleens. About 60% of decidual Treg cells were Tim-3 positive at E6.5. Of these decidual Tim3+ Treg cells, nearly 90% were PD-1 positive. However, only about 16% of Tim3− Treg cells expressed PD-1. Blocking the Tim-3 signaling pathway decreased the proportion of Treg cells and led to embryo resorption. Moreover, much lower Tim-3 expression was observed on CD4+ T cells and Treg cells in women who had suffered from RPL at 6–9 gestational weeks compared with those who had normal pregnancies at matched gestations. In a normal pregnancy, Tim-3 expression on decidual CD4+ T cells is induced initially by IL-27. Then Gal-9-Tim-3 interaction promotes differentiation of decidual Tim-3+ CD4+ T cells into Treg cells. IL-27 and Gal-9 cooperatively induced Tim-3+ Treg cells in vitro. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION We did not investigate the kinetics of human decidual Tim-3+ CD4+ T and Tim-3+ Treg cell populations throughout pregnancy due to limited availability of second and third trimester decidua. In addition, functional suppressive data on the decidual Tim-3+ Treg cells are lacking due to limited and low quantities of these cells in decidua. WIDER IMPLICATIONS OF THE FINDINGS These findings might have therapeutic clinical implications in RPL. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by research grants from the National Natural Science Foundation of China (No. 81871186) and National Key Research & Developmental Program of China (2018YFC1003900, 2018YFC1003904). The authors declare no conflict of interest.

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mTOR pathway regulates the differentiation of peripheral blood Th2/Treg cell subsets in patients with pemphigus vulgaris

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/gmab008 ◽

2021 ◽

Author(s):

Kuan Lai ◽

Wenjing Zhang ◽

Songshan Li ◽

Zhiwen Zhang ◽

Shuangde Xie ◽

...

Keyword(s):

T Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Pemphigus Vulgaris ◽

Treg Cells ◽

Mtor Pathway ◽

Cd4 T Cell ◽

Cell Ratio ◽

Loss Of Balance

Abstract Pemphigus vulgaris (PV) is a chronic and potentially life-threatening autoimmune blistering disease. Aberrant mTOR pathway activity is involved in many autoimmune diseases. This study investigated the correlation of mTOR pathway (PI3K/AKT/mTOR/p70S6K) activity with the loss of balance in T helper 2/regulatory T (Th2/Treg) cells in the peripheral blood of PV patients. CD4+ T cells were isolated from 15 PV patients and 15 healthy controls (HCs), the ratios of Th2/CD4+ T cells and Treg/CD4+ T cells, the activity of the mTOR pathway (PI3K/AKT/mTOR/p70S6K), the transcription factors and cytokines of Th2 and Treg cells were detected. Primary CD4+ T cells from PV patients were cultured under Th2- or Treg-polarizing conditions with or without rapamycin in vitro. We found that PV patients showed significantly elevated serum IL-4 when compared with HCs, and serum IL-4 level was positively correlated with the titer of anti-Dsg1/3 antibody and disease severity, while the serum TGF-β level was negatively correlated with the titer of anti-Dsg3 antibody and disease severity. Meanwhile, PV patients showed increased Th2/CD4+ T cell ratio; decreased Treg/CD4+ T cell ratio; elevated mRNA of PI3K, AKT, mTOR and protein of PI3K (P85), AKT, p-AKT (Ser473), mTOR, p-mTOR (Ser2448), p-p70S6K (Thr389), GATA3; reduced protein of forkhead box protein 3. Rapamycin inhibited Th2 cell differentiation and promoted Treg cell differentiation in vitro. These data suggest a close association between mTOR pathway activation and the loss of balance in Th2/Treg cells in peripheral blood of PV patients. Inhibiting mTORC1 can help restore the Th2/Treg balance.

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Universal CD137 Expression upon Activation Allows Efficient Isolation of a Broad Repertoire of Virus-Specific CD8+ and CD4+ T Cells for Adoptive Immunotherapy.

Blood ◽

10.1182/blood.v112.11.2222.2222 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2222-2222

Author(s):

Maarten L. Zandvliet ◽

J.H. Frederik Falkenburg ◽

Inge Jedema ◽

Roelof Willemze ◽

Henk-Jan Guchelaar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

Cell Populations ◽

T Cell Lines ◽

Kinetics Of ◽

Ifng Production

Abstract Reactivation of adenovirus (ADV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) can cause serious morbidity and mortality during the prolonged period of immune deficiency following allogeneic stem cell transplantation. It has been shown that adoptive transfer of donor-derived virus-specific T cells can be a successful strategy to control viral reactivation. To provide safe and effective anti-viral immunotherapy, we aimed to generate combined CD8+ and CD4+ T cell lines with high specificity for a broad range of viral epitopes. Isolation by the IFNg capture assay of virus-specific T cells that produce IFNg upon activation allows the generation of highly specific T cell lines without the need for extensive culture. However, it has been recently shown that specific upregulation of the co-stimulatory molecule CD137 upon antigen-specific activation of CD8+ and CD4+ T cells can also be used for isolation. We therefore analyzed IFNg production and CD137 expression by CD8+ and CD4+ T cells upon incubation of peripheral blood mononuclear cells (PBMC) from seropositive donors with peptides corresponding to 17 defined MHC class I restricted minimal epitopes from 10 different ADV, CMV, EBV and influenza (FLU) proteins, and 15-mer or 30-mer peptides containing MHC class II restricted epitopes from CMV pp65 or ADV hexon. Using tetramer and intracellular IFNg staining we first determined the fraction of CD8+ T cells that produced IFNg upon activation with the minimal epitopes. Specific IFNg production was observed for 58–100% of tetramer+ CD8+ T cells specific for CMV pp65 (n=6), and 83% for FLU (n=1), but only 18–58% for CMV pp50 (n=3) or IE-1 (n=3), 4–91% for EBV latent (n=3) and lytic (n=3) epitopes, and 41–63% for ADV hexon (n=2). In contrast to the variation in the fraction of IFNg-producing cells, we observed homogeneous upregulation of CD137 by the virus-specific tetramer+ T cell populations upon activation. In 2 cases where no CD137 expression by tetramer+ T cells could be detected, no IFNg production was observed either. These data suggest that the majority of CD8+ T cells specific for CMV pp65 or FLU can be isolated on basis of IFNg production, but only part of CD8+ T cell populations specific for other viral proteins, while complete virus-specific CD8+ T cell populations may be isolated on basis of CD137 expression. Activation of CD4+ T cells specific for CMV pp65 or ADV hexon with 15-mer or 30-mer peptides induced both specific IFNg production and CD137 expression. To investigate whether multiple virus-specific T cell populations could be isolated simultaneously, we next determined the kinetics of IFNg production after activation with defined MHC class I epitopes or peptides containing MHC class II epitopes. CMV- and EBV-specific CD8+ T cells and CMV-specific CD4+ T cells showed a rapid induction of IFNg production, which peaked after 4 hours and decreased thereafter. In contrast, ADV- and FLU-specific CD8+ T cells and ADV-specific CD4+ T cells, predominantly having a more early differentiation phenotype (CD27+CD28+) compared to CMV- and EBV-specific T cells, showed peak IFNg production after 8 hours that continued for more than 48 hours. This difference in phenotype and IFNg kinetics may suggest that the persistent and frequent presentation of CMV and EBV epitopes in vivo, in contrast to an intermittent exposure to ADV and FLU epitopes, drives differentiation and shapes the kinetics of the IFNg response of specific T cells. Kinetic analysis of CD137 expression showed uniform upregulation by virus-specific CD8+ T cell populations from day 1 to day 4 after activation, which peaked at day 2, suggesting that this may be the optimal time point for CD137-based isolation. In a limited number of experiments, virus-specific CD8+ and CD4+ T cells could be isolated based on CD137 expression within the same timeframe. These data indicate that virus-specific T cell populations can be more efficiently isolated at one time point on basis of CD137 expression than on basis of IFNg production, due to differences in IFNg kinetics. In conclusion, this study shows that T cell lines generated by CD137 isolation may comprise a significant number of virus-specific T cells which do not produce IFNg, but may have other effector functions. Furthermore, CD137-based enrichment may be more robust and allows the efficient simultaneous isolation of multiple virus-specific T cell populations due to uniform kinetics of CD137 expression.

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Nonredundant roles for Stat5a/b in directly regulating Foxp3

Blood ◽

10.1182/blood-2006-11-055756 ◽

2007 ◽

Vol 109 (10) ◽

pp. 4368-4375 ◽

Cited By ~ 391

Author(s):

Zhengju Yao ◽

Yuka Kanno ◽

Marc Kerenyi ◽

Geoffrey Stephens ◽

Lydia Durant ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Cell Fate ◽

Cd4 T Cells ◽

Fetal Liver ◽

Treg Cells ◽

Signal Transducers ◽

Fetal Liver Cells ◽

Complete Deletion

Abstract Stats (signal transducers and activators of transcription) regulate multiple aspects of T-cell fate. T regulatory (Treg) cells are a critical subset that limits immune responses, but the relative importance of Stat5a/b versus Stat3 for Treg cell development has been contentious. We observed that peripheral CD25+CD4+ T cells were reduced in Stat5ΔN mice; however, the levels of Foxp3, a transcription factor that is critical for Treg cells, were normal in splenic CD4+ T cells even though they were reduced in the thymus. In contrast, complete deletion of Stat5a/b (Stat5−/−) resulted in dramatic reduction in CD25- or Foxp3-expressing CD4+ T cells. An intrinsic requirement was demonstrated by reduction of Stat5a/b in CD4-expressing cells and by stem cell transplantation using Stat5−/− fetal liver cells. Stat5a/b were also required for optimal induction of Foxp3 in vitro and bound directly to the Foxp3 gene. Reduction of Stat3 in T cells did not reduce the numbers of Treg cells in the thymus or spleen; however, Stat3 was required for IL-6–dependent down-regulation of Foxp3. Therefore, we conclude that Stat5a/b have an essential, nonredundant role in regulating Treg cells, and that Stat3 and Stat5a/b appear to have opposing roles in the regulation of Foxp3.

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Mapping Rora expression in resting and activated CD4+ T cells

PLoS ONE ◽

10.1371/journal.pone.0251233 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0251233

Author(s):

Liora Haim-Vilmovsky ◽

Johan Henriksson ◽

Jennifer A. Walker ◽

Zhichao Miao ◽

Eviatar Natan ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Treg Cells ◽

Negative Regulator ◽

Th2 Cells ◽

Nippostrongylus Brasiliensis ◽

Rna Seq ◽

Infection Models

The transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells in general, but with an emphasis on Th2 cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4+ T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment.

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Characterization of immunoactive and immunotolerant CD4+ T cells in breast cancer by measuring activity of signaling pathways that determine immune cell function

10.1101/2020.10.08.292557 ◽

2020 ◽

Author(s):

Yvonne Wesseling-Rozendaal ◽

Arie van Doorn ◽

Karen Willard-Gallo ◽

Anja van de Stolpe

Keyword(s):

Breast Cancer ◽

Signal Transduction ◽

Immune Response ◽

T Cells ◽

Cd4 T Cells ◽

Treg Cells ◽

Cd4 T Cell ◽

Cancer Tissue ◽

Pathway Activity

AbstractCancer immunotolerance can be reversed by checkpoint blockade immunotherapy in some patients, but response prediction remains a challenge. CD4+ T cells play an important role in activating adaptive immune responses against cancer. Conversion to an immune suppressive state impairs the anti-cancer immune response and is mainly effected by CD4+ Treg cells. A number of signal transduction pathways activate and control functions of CD4+ T cell subsets. As previously described, assays have been developed which enable quantitative measurement of the activity of signal transduction pathways (e.g. TGFβ, NFκB, PI3K-FOXO, JAK-STAT1/2, JAK-STAT3, Notch) in a cell or tissue sample. Using these assays, pathway activity profiles for various CD4+ T cell subsets were defined and cellular mechanisms underlying breast cancer-induced immunotolerance investigated in vitro. Results were used to measure the immune response state in a clinical breast cancer study.MethodsSignal transduction pathway activity scores were measured on Affymetrix expression microarray data of resting, immune-activated, and immune-activated CD4+ T cells incubated with breast cancer tissue supernatants, and of CD4+ Th1, Th2, and Treg cells, and in a clinical study in which CD4+ T cells were derived from blood, lymph node and cancer tissue from primary breast cancer patients (n=10).ResultsIn vitro CD4+ T cell activation induced PI3K, NFκB, JAK-STAT1/2, and JAK-STAT3 pathway activity. Simultaneous incubation with primary cancer supernatant reduced PI3K and NFκB, and partly reduced JAK-STAT3, pathway activity, while simultaneously increasing TGFβ pathway activity; characteristic of an immune tolerant state. CD4+ Th1, Th2, and Treg cells all had a specific pathway activity profile, with activated immune suppressive Treg cells characterized by NFκB, JAK-STAT3, TGFβ, and Notch pathway activity. An immune tolerant pathway profile was identified in CD4+ T cells from tumor infiltrate of a subset of primary breast cancer patients which could be contributed to activated Treg cells. A Treg pathway profile was also identified in blood samples.ConclusionSignaling pathway assays can be used to quantitatively measure the functional immune response state of lymphocyte subsets in vitro and in vivo. Clinical results suggest that in primary breast cancer the adaptive immune response of CD4+ T cells has frequently been replaced by immunosuppressive Treg cells, potentially causing resistance to checkpoint inhibition. In vitro study results suggest that this effect is mediated by soluble factors from cancer tissue (e.g. TGFβ). Signaling pathway activity analysis on TIL and/or blood samples is expected to improve predicting and monitoring response to checkpoint inhibitor immunotherapy.

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The relationship between human thymus-derived regulatory T cells, TGF-β-induced regulatory T cells and conventional CD4+ T cells as revealed by proteomics

10.1101/2021.10.30.466569 ◽

2021 ◽

Author(s):

Mark Mensink ◽

Ellen Schrama ◽

Maartje van den Biggelaar ◽

Derk Amsen ◽

Jannie Borst ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Protein Expression ◽

Treg Cell ◽

Ex Vivo ◽

Foxp3 Expression ◽

Treg Cells ◽

Cell Populations ◽

The Relationship

The CD4+ regulatory T (Treg) cell lineage, as defined by FOXP3 expression, comprises thymus-derived (t)Treg cells and peripherally induced (p)Treg cells. In human, naive tTreg cells can be purified from blood, but occur in low abundance, while effector pTreg and tTreg cell populations cannot be purified for lack of discriminating cell surface markers. Therefore, studies often employ TGF-β-induced (i)Treg cells that are generated from CD4+ conventional T (Tconv) cells in vitro. Here, we describe the relationship of iTreg cells to tTreg and Tconv cells, as optimally purified from human blood. Global proteomic analysis revealed that iTreg, tTreg and Tconv cell populations each have a unique protein expression pattern. We next used as a benchmark a previously defined proteomic signature that discerns ex vivo naive and effector phenotype Treg cells from Tconv cells and reflects unique Treg cell properties. This Treg cell core signature was largely absent from iTreg cells, while clearly present in simultaneously analyzed tTreg cells. In addition, we used a proteomic signature that distinguishes ex vivo effector Treg cells from Tconv cells and naive Treg cells. This effector Treg cell signature was partially present in iTreg cells. Thus, iTreg cells are distinct from tTreg cells and largely lack the common Treg cell proteomic signature. However, they do have certain protein expression features in common with ex vivo effector Treg cells. These data demonstrate the utility of the core and effector Treg cell signatures as tools to define Treg cell populations and encourage the use of ex vivo Treg cells for functional analyses.

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Rora regulates activated T helper cells during inflammation

10.1101/709998 ◽

2019 ◽

Cited By ~ 3

Author(s):

Liora Haim-Vilmovsky ◽

Johan Henriksson ◽

Jennifer A Walker ◽

Zhichao Miao ◽

Eviatar Natan ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Treg Cells ◽

Negative Regulator ◽

Nippostrongylus Brasiliensis ◽

Rna Seq ◽

Infection Models

AbstractThe transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4+ T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment.

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Induction of regulatory T cell–resistant helper CD4+ T cells by bacterial vector

Blood ◽

10.1182/blood-2007-09-113761 ◽

2008 ◽

Vol 111 (3) ◽

pp. 1404-1412 ◽

Cited By ~ 24

Author(s):

Hiroyoshi Nishikawa ◽

Takemasa Tsuji ◽

Elke Jäger ◽

Gabriel Briones ◽

Gerd Ritter ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Treg Cells ◽

Th1 Cells ◽

High Avidity ◽

T Helper 1 ◽

Bacterial Vector ◽

Healthy Donors

Abstract Salmonella typhimurium engineered to deliver cancer/testis antigen NY-ESO-1 through type III secretion (S typhimurium–NY-ESO-1) was shown to be an efficient cancer vaccine construct in mice and to stimulate NY-ESO-1–specific CD8+/CD4+ T cells in vitro in patients with cancer with NY-ESO-1 spontaneous immunity. We also showed that individuals without spontaneous immunity to NY-ESO-1 had specific CD4+ T-cell precursors with high avidity to NY-ESO-1 under tight control by CD4+CD25+ regulatory T (Treg) cells. We now found that in healthy donors and patients with melanoma without NY-ESO-1 spontaneous immunity, S typhimurium–NY-ESO-1 elicits CD4+ T helper 1 (Th1) cells in vitro recognizing naturally processed antigen from these high-avidity NY-ESO-1–specific naive precursors. In contrast to peptide stimulation, induction of specific Th1 cells with S typhimurium–NY-ESO-1 did not require in vitro depletion of CD4+CD25+ Treg cells, and this prevailing effect was partially blocked by disruption of interleukin-6 or glucocorticoid-induced TNF receptor (GITR) signals. Furthermore, S typhimurium–induced Th1 cells had higher GITR expression than peptide-induced Th1 cells and were resistant to suppression by CD4+CD25+ Treg cells in a GITR-dependent fashion. We propose that S typhimurium–NY-ESO-1 induces antigen-specific T-cell responses that are resistant to suppression by CD4+CD25+ Treg cells.

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Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells

Journal of Experimental Medicine ◽

10.1084/jem.20100799 ◽

2011 ◽

Vol 208 (2) ◽

pp. 235-249 ◽

Cited By ~ 77

Author(s):

Masako Saito ◽

Masayuki Nagasawa ◽

Hidetoshi Takada ◽

Toshiro Hara ◽

Shigeru Tsuchiya ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Cd4 T Cells ◽

Elevated Serum ◽

Treg Cells ◽

Th2 Cells ◽

Hyper Ige Syndrome ◽

And Function

Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17–producing CD4+ T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (Treg cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of Treg cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10–treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4+ T cells to FOXP3+ induced Treg cells (iTreg cells). These results suggest that the defective generation of IL-10–induced tolerogenic DCs and iTreg cells may contribute to inflammatory changes in HIES.

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In Vivo Activated CD103+CD4+ Regulatory T Cells Ameliorate Ongoing Chronic GVHD.

Blood ◽

10.1182/blood.v110.11.350.350 ◽

2007 ◽

Vol 110 (11) ◽

pp. 350-350

Author(s):

Dongchang Zhao ◽

Chunyan Zhang ◽

Tangsheng Yi ◽

Chia-Lei Lin ◽

Ivan Todorov ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Cd4 T Cells ◽

Chronic Gvhd ◽

Treg Cells ◽

Dependent Manner ◽

T And B Cells ◽

Ifn Γ

Abstract The αEβ7 integrin CD103 is an excellent marker for identifying in vivo activated CD4+ regulatory T (Treg) cells. CD103− naive Treg cells from donors are effective in prevention but ineffective in treatment of graft versus host disease (GVHD). It is unknown whether in vivo activated donor CD103+ Treg cells can effectively treat ongoing GVHD. We have recently reported a new chronic GVHD model, in which donor DBA/2 (H-2d) spleen cells were transferred to the irradiated BALB/c (H-2d) recipients. The recipients showed chronic GVHD-like syndrome with high-levels of serum autoantibodies, proteinuria, and hair-loss, and the disease induction required both donor CD4+ T and B cells in a cell dose dependent manner (Blood, 2006). In the current studies, we observed that the percentage of CD103+ cells among donor CD4+ T cells in the recipients without disease was up to 45% and was more than two fold higher than that of the recipients with disease. The CD103+CD4+ T cells were more than 97% FoxP3+, which was similar to natural CD25hi Treg cells, but the former expressed markedly higher levels of CCR5 as compared to the latter. The CD103+ Treg cells showed markedly stronger suppression capacity as compared to freshly isolated as well as in vitro anti-CD3-activated CD25hi natural Treg cells. When injected into ongoing chronic GVHD recipients with severe proteinuria, CD103+ Treg cells (1x106) reversed proteinuria and tissue damages in 92% (11/12) of the recipients, and the recipients survived for more than 100 days. In contrast, the in vitro activated natural Treg cells reversed disease in only 25% (2/8) of the recipients, and the freshly isolated CD25hi natural Treg cells reversed none (0/12), and the treated recipients died within 45 days, which was similar to control PBS treated recipients. Furthermore, we found that infusion of the CD103+ Treg cells significantly reduced CD138+ antibody-secreting plasma cells in spleen and reduced serum levels of autoantibodies; and that infusion of the CD103+ Treg cells also significantly reduced CD44loCD62LhiSCA-1hi post-mitotic CD4+ T memory stem cells in spleen as well as pathogenic IFN-γ+CD4+ T cells in liver and nephritogenic IFN-γ+IL-10+CD4+ T cells in kidney tissues. Our results indicate that, different from CD103− naive natural Treg cells that prevent GVHD via suppressing donor T cell activation and expansion, CD103+ Treg cells ameliorate ongoing chronic GVHD via reducing activated pathogenic T and B cells.

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