Lung Injury Combined with Loss of Regulatory T Cells Leads to De Novo Lung-Restricted Autoimmunity

Recurrent pregnancy loss (RPL) is one of the most common complications of early pregnancy associated in most cases with local or systemic immune abnormalities such as the diminished proportion of regulatory T cells (Tregs). Mesenchymal stem cells (MSCs) have been shown to modulate immune responses by de novo induction and expansion of Tregs. In this study, we analyzed the molecular and cellular mechanisms involved in Treg-associated pregnancy protection following MSCs administration in an abortion-prone mouse mating. In a case-control study, syngeneic abdominal fat-derived MSCs were administered intraperitoneally (i.p) to the DBA/2-mated CBA/J female mice on day 4.5 of pregnancy. Abortion rate, Tregs proportion in spleen and inguinal lymph nodes, and Ho1, Foxp3, Pd1, and Ctla4 genes expression at the feto-maternal interface were then measured on day 13.5 of pregnancy using flow cytometry and quantitative RT- PCR, respectively. The abortion rate in MSCs-treated mice was significantly reduced and normalized to the level observed in normal pregnant animals. We demonstrated a significant induction of Tregs in inguinal lymph nodes but not in the spleen following MSCs administration. Administration of MSCs remarkably upregulated the expression of HO1, Foxp3, Pd1, and Ctla4 genes in both placenta and decidua. Here, we show that MSCs therapy could protect the fetus in the abortion-prone mice through Tregs expansion and up-regulation of Treg-related genes. These events could establish an immune-privileged microenvironment, which participates in regulation of detrimental maternal immune responses against the semi-allogeneic fetus.

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Mesenteric lymph node stromal cell-derived extracellular vesicles contribute to peripheral de novo induction of Foxp3+ regulatory T cells

European Journal of Immunology ◽

10.1002/eji.201746960 ◽

2017 ◽

Vol 47 (12) ◽

pp. 2142-2152 ◽

Cited By ~ 5

Author(s):

Maria Pasztoi ◽

Joern Pezoldt ◽

Michael Beckstette ◽

Christoph Lipps ◽

Dagmar Wirth ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

Regulatory T Cells ◽

Extracellular Vesicles ◽

Mesenteric Lymph Node ◽

Stromal Cell ◽

De Novo ◽

Mesenteric Lymph

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Recovery from acute lung injury can be regulated via modulation of regulatory T cells and Th17 cells

Scandinavian Journal of Immunology ◽

10.1111/sji.12715 ◽

2018 ◽

Vol 88 (5) ◽

pp. e12715 ◽

Cited By ~ 6

Author(s):

Linlin Wang ◽

Xiaocen Wang ◽

Lin Tong ◽

Jian Wang ◽

Maosen Dou ◽

...

Keyword(s):

T Cells ◽

Acute Lung Injury ◽

Regulatory T Cells ◽

Lung Injury ◽

Th17 Cells

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Expansion and de novo generation of potentially therapeutic regulatory T cells in patients with autoimmune hepatitis

Hepatology ◽

10.1002/hep.22071 ◽

2008 ◽

Vol 47 (2) ◽

pp. 581-591 ◽

Cited By ~ 85

Author(s):

Maria Serena Longhi ◽

Francesca Meda ◽

Pengyun Wang ◽

Marianne Samyn ◽

Giorgina Mieli-Vergani ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Autoimmune Hepatitis ◽

De Novo

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De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0407691102 ◽

2005 ◽

Vol 102 (11) ◽

pp. 4103-4108 ◽

Cited By ~ 227

Author(s):

M. R. Walker ◽

B. D. Carson ◽

G. T. Nepom ◽

S. F. Ziegler ◽

J. H. Buckner

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

De Novo

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Homeostatic Expansion of Donor FoxP3+ CD25+CD4+ T Cells in Recipients of CD4+ Cells Depleted Allogeneic Hematopoietic Graft.

Blood ◽

10.1182/blood.v108.11.3207.3207 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3207-3207

Author(s):

Mohammad S. Hossain ◽

Cynthia R. Giver ◽

Ned Waller

Keyword(s):

Weight Loss ◽

T Cells ◽

Stem Cell ◽

Regulatory T Cells ◽

Cd4 T Cells ◽

De Novo ◽

Clinical Signs ◽

Post Transplant ◽

Allogeneic Bmt ◽

Homeostatic Expansion

Abstract Background: In allogeneic BMT patients, the presence of allo-reactive donor CD4+ T cells in the graft were reported to be the primary cause of GvHD. Moreover, donor T-cells are required to promote the stem cell engraftment and to decrease the disease relapse. A number of studies also reported that a subset of CD4+CD25+ T cells usually generated de novo from the thymus that expressed FoxP3 regulate the T cells allo-reactivity in vivo. Thus, to establish a therapeutically useful adoptive T-cells immunotherapy, we depleted the CD4+ T cells from the graft and transplanted along with T cell depleted (TCD) BM cells in clinically relevant parent to F1 experimental allogeneic BMT model. Our hypothesis is that CD4-depleted graft will not cause GvHD, preserve the thymic function, homeostatically produce donor BM-derived CD4+ T cells along with FoxP3+CD4+CD25+ regulatory T cells with beneficial anti-opportunistic infection and anti-tumor effects. Methods: We used a parent (C57BL/6) to (C57BL/6 X BALB/c)CB6F1 allogeneic BMT model with a combination of TCD BM and splenocytes as the hematopoietic graft. CD4+ or CD8+ cells were selectively depleted from the splenocytes of C57BL/6 donor mice using MACS column. 1×106 CD4-depleted splenocytes or a mixture of 2×106 CD8-depleted and 1×106 CD4-depleted splenocytes and/or grafts containing 10×106 unfractionated splenocytes along with 5×106 TCD BM cells harvested from the congeneic C57BL/6 donor mice, were adoptively transferred to lethally irradiated (11Gy) CB6F1 mice. GvHD was monitored twice weekly by weight loss and other clinical signs. After 50 days post transplant recipients mice were bled or sacrificed and lymphocytes isolated from blood and different organs were analyzed by multicolor FACS. Results: Within 50 days of transplant the recipients of CD4-depleted splenocytes had 100% survival without GvHD whereas recipients of mixture of CD4- and CD8-depleted splenocytes or unfractionated splenocytes suffered from severe GvHD (%weight loss below 20%) with 50% survival. Surprisingly, very significantly expansion of total CD4+ T cells (37% ± 7% of lymphocytes, CD4:CD8 ratio 6:1) occurred in the blood of recipients of CD4-depleted splenocytes. In contrast the recipients of mixture of CD4- and CD8-depleted splenocytes DLI or whole splenocytes had only few CD4+ T cells (~2% ± 2% of lymphocytes, CD4:CD8 ratio 1:2). Over 90% of the CD4+ T cells in the blood of recipients of CD4-depleted splenocytes were from the donor BM and included significantly higher number of CD25+CD4+ T cells compared with the recipients of mixture of CD4- and CD8-depleted splenocytes or unfractionated splenocytes. Similarly, significantly increased numbers of FoxP3+CD25+CD4+ regularity T cells were also found in the spleen and thymus of recipients of CD4-depleted splenocytes compared with the recipients of mixture of CD4- and CD8-depleted splenocytes or unfractionated splenocytes (p<0.005). Conclusion: Adoptive immunotherapy with the CD4-depleted hematopoietic graft results better immune reconstitution, caused extensive homeostatic expansion of donor stem cell-derived CD4+ T cells including significantly increased levels of FoxP3+CD25+ CD4+ regulatory T cells derived from de novo thymopoiesis without GvHD. The presence of donor FoxP3+CD25+ CD4+ regulatory T cells in the hematopoietic graft are not necessary for post-transplant expansion of donor stem-cell-derived regulatory T-cells via thymopoiesis.

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Regulatory T Cells Expanded by Autologous Mature Human Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase Are Potent Suppressors of T Cell Proliferation.

Blood ◽

10.1182/blood.v112.11.1553.1553 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1553-1553

Author(s):

Davi d J. Chung ◽

Marco Rossi ◽

Emanuela Romano ◽

Jennifer Pressley ◽

Christophe Antczak ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Regulatory T Cells ◽

De Novo ◽

T Cell Proliferation ◽

Indoleamine 2,3 Dioxygenase ◽

Naturally Occurring ◽

Dose Dependent

Abstract Best characterized as initiators of immunity, dendritic cells (DCs) also play an integral role in immune modulation. Immature DCs, for example, process self-antigens to induce and maintain tolerance. The immunoregulatory effects of DCs, however, are not limited to immature subtypes. Immunogenic mature DCs can also induce T regs to curb immune responses. We have found that human monocyte-derived DCs (moDCs) upregulate the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) with maturation and expand functionally active, naturally occurring as well as inducible regulatory T cells (T regs) in an IDO-dependent manner. Priming of resting bulk T cells with autologous, IDO-expressing, mature moDCs in the absence of exogenous cytokines results in up to 10-fold expansion of CD4+CD25hiFoxp3+CD127neg T cells that mediate significant dose-dependent suppression of both allogeneic and autologous T cells stimulated de novo by DCs. The expansion of T regs by IDO-expressing moDCs involves cell-to-cell contact, CD80/CD86 ligation, and IL-2. Autologous priming in the presence of a competitive inhibitor of IDO, 1-methyl-tryptophan, diminishes T reg expansion. Candidate T regs were further characterized after cytofluorographic sorting primed bulk T cells into CD4+CD25hi, CD4+CD25int, and CD4+CD25neg subpopulations. Post-sort analysis showed that >60% of the CD4+CD25hi cells coexpressed Foxp3, which was not present in the CD4+CD25neg cells. CD4+CD25hi T regs exerted dose-dependent inhibition of DC-stimulated allogeneic T cell proliferation, with >90% inhibition at a suppressor to responder T cell ratio of 1:1 and ~50% inhibition at a ratio of 1:25. CD4+CD25int cells produced intermediate suppression depending on dose, and CD4+CD25neg cells were not inhibitory. CD4+CD25hi T regs mediated similar suppression of autologous T cell responses to stimulation de novo by DCs. CD4+CD25hi T regs also inhibited the generation of cytotoxic T lymphocytes (CTLs) specific for the Wilms’ tumor gene product (WT-1). The addition of CD4+CD25hi T regs to CTL-priming cultures resulted in a >80% decrease in specific target cell lysis of a WT-1-expressing cell line. Separate studies showed that T reg-mediated suppression is contact dependent and also requires TGF-beta, suggesting inhibition by naturally occurring and inducible T regs, respectively. Depletion of CD4+CD25hi T cells from bulk T cells by negative immunoselection with anti-CD25 magnetic beads at the outset of autologous priming significantly blunts T reg expansion, indicating a requirement for pre-existing T regs in the bulk T cell population. T reg expansion also occurs in priming cultures using cytofluorographically-sorted CD4+CD25neg T cells, indicating de novo generation of T regs from CD4+CD25neg precursors. In summary, our results demonstrate a mechanism by which mature, IDO-expressing, human moDCs expand autologous, naturally occurring as well as inducible T regs that functionally suppress the proliferation of both autologous and allogeneic T cells. Inhibition of this counter-regulatory pathway should result in more sustained benefit from active DC-based immunotherapy.

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