Xenospecific regulatory T cells generated on porcine B cells are capable in controlling xenogeneic immune responses in humanized mice

2014 ◽  
Vol 21 (2) ◽  
pp. 187-187
Author(s):  
Yun-Shien Lee ◽  
Fatih Noyan ◽  
Mathias Hardtke-Wolenski ◽  
Ann-Kathrin Knoefel ◽  
Richard Taubert ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Humanized Mice

Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse

Blood ◽  
2007 ◽  
Vol 110 (5) ◽  
pp. 1519-1529 ◽  
Author(s):  
Peter Reichardt ◽  
Bastian Dornbach ◽  
Song Rong ◽  
Stefan Beissert ◽  
Faikah Gueler ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
B Cell ◽  
Dependent Manner ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Immunologic Synapse

Abstract Naive B cells are ineffective antigen-presenting cells and are considered unable to activate naive T cells. However, antigen-specific contact of these cells leads to stable cell pairs that remain associated over hours in vivo. The physiologic role of such pairs has not been evaluated. We show here that antigen-specific conjugates between naive B cells and naive T cells display a mature immunologic synapse in the contact zone that is absent in T-cell–dendritic-cell (DC) pairs. B cells induce substantial proliferation but, contrary to DCs, no loss of L-selectin in T cells. Surprisingly, while DC-triggered T cells develop into normal effector cells, B-cell stimulation over 72 hours induces regulatory T cells inhibiting priming of fresh T cells in a contact-dependent manner in vitro. In vivo, the regulatory T cells home to lymph nodes where they potently suppress immune responses such as in cutaneous hypersensitivity and ectopic allogeneic heart transplant rejection. Our finding might help to explain old observations on tolerance induction by B cells, identify the mature immunologic synapse as a central functional module of this process, and suggest the use of naive B-cell–primed regulatory T cells, “bTregs,” as a useful approach for therapeutic intervention in adverse adaptive immune responses.

Naturally Occurring Regulatory T Cells Modulate Immune Responses Against Exogenous Factor VIII in Hemophilic Balb/c Mice but Not in C57BL/6J Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1160-1160
Author(s):  
Christina Hausl ◽  
Josenato Ilas ◽  
Christian Lubich ◽  
Rafi U. Ahmad ◽  
Eva M. Muchitsch ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Factor Viii ◽  
Matched Control ◽  
Antibody Responses ◽  
Protein Antigens ◽  
Naturally Occurring

Abstract Antibody responses against factor VIII (FVIII) are the major complication that arises when patients with hemophilia A are treated with factor VIII products. Therefore, understanding regulation of anti-FVIII immune responses is of outmost importance. Antibody responses are well established to result from differentiation of B cells into antibody-secreting plasma cells. B cells need help from activated CD4+ T cells to develop high-affinity antibody responses against protein antigens such as FVIII. Recently, naturally occurring CD4+CD25+ regulatory T cells have been shown to modulate antibody responses by either suppressing the function of CD4+ T helper cells or by directly acting on B cells. However, the potential importance of CD4+CD25+ T cells in regulating antibody responses to foreign protein antigens is controversial. Furthermore, the extent to which naturally occurring CD4+CD25+ T cells regulate antibody responses against exogenous proteins such as FVIII when these proteins are given to previously untreated patients is unclear. To obtain information on how important naturally occurring CD4+CD25+ T cells are under such conditions, we asked whether these cells regulate anti-FVIII antibody responses in murine hemophilia A. We studied E17 hemophilic mice with two different genetic backgrounds (C57BL/6J and Balb/c) and treated them with four intravenous doses of human FVIII given at weekly intervals. Before the first dose of FVIII, CD4+CD25+ T cells were depleted in vivo using an anti-CD25 antibody that has been shown to deplete naturally occurring CD4+CD25+ T cells in mice. In vivo depletion of regulatory T cells using the same antibody has been successfully applied in a variety of mouse studies to evaluate the significance of naturally occurring CD4+CD25+ T cells in different immunological systems. An isotype-matched control antibody was used as a negative control. A week after the second and the fourth dose of FVIII, plasma samples were taken and tested for anti-FVIII antibodies. We found differences in titers of anti-FVIII antibodies between mice treated with anti-CD25 antibodies and control mice in Balb/c mice but not in C57BL/6J mice. Hemophilic Balb/c mice that had been pre-treated with anti-CD25 antibodies developed higher titers of anti-FVIII antibodies than mice that had been pre-treated with an isotype-matched control antibody. Differences were seen as a statistical trend (p=0.091) after two doses of FVIII and reached statistical significance (p=0.024) after four doses of FVIII. No differences in antibody titers were observed in hemophilic C57BL/6J mice. Our results strongly indicate that the ability of naturally occurring regulatory T cells to modulate anti-FVIII antibody responses in hemophilic mice depends on the genetic background of these mice. Immunoregulatory factors such as cytokines or chemokines as well as differences in the number and functional activity of naturally occurring regulatory T cells that are found in secondary lymphoid organs are likely to determine the regulatory capacity of these cells. Based on our results we conclude that differences in number and functional activity of naturally occurring regulatory T cells should be considered in the search for risk factors associated with the development of FVIII inhibitors in patients.

Donor-specific Regulatory T Cells Generated on Donor B Cells Are Superior to CD4+CD25high Cells in Controlling Alloimmune Responses in Humanized Mice

2013 ◽  
Vol 45 (5) ◽  
pp. 1832-1837 ◽  
Author(s):  
F. Noyan ◽  
Y.-S. Lee ◽  
M. Hardtke-Wolenski ◽  
A.-K. Knoefel ◽  
R. Taubert ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Humanized Mice

scholarly journals Selective Induction of Th2-Attracting Chemokines CCL17 and CCL22 in Human B Cells by Latent Membrane Protein 1 of Epstein-Barr Virus

2004 ◽  
Vol 78 (4) ◽  
pp. 1665-1674 ◽  
Author(s):  
Takashi Nakayama ◽  
Kunio Hieshima ◽  
Daisuke Nagakubo ◽  
Emiko Sato ◽  
Masahiro Nakayama ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Regulatory T Cells ◽  
Epstein Barr Virus ◽  
Cytotoxic T Cells ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Chemokines are likely to play important roles in the pathophysiology of diseases associated with Epstein-Barr virus (EBV). Here, we have analyzed the repertoire of chemokines expressed by EBV-infected B cells. EBV infection of B cells induced expression of TARC/CCL17 and MDC/CCL22, which are known to attract Th2 cells and regulatory T cells via CCR4, and also upregulated constitutive expression of MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5, which are known to attract Th1 cells and cytotoxic T cells via CCR5. Accordingly, EBV-immortalized B cells secreted these chemokines, especially CCL3, CCL4, and CCL22, in large quantities. EBV infection or stable expression of LMP1 also induced CCL17 and CCL22 in a B-cell line, BJAB. The inhibitors of the TRAF/NF-κB pathway (BAY11-7082) and the p38/ATF2 pathway (SB202190) selectively suppressed the expression of CCL17 and CCL22 in EBV-immortalized B cells and BJAB-LMP1. Consistently, transient-transfection assays using CCL22 promoter-reporter constructs demonstrated that two NF-κB sites and a single AP-1 site were involved in the activation of the CCL22 promoter by LMP1. Finally, serum CCL22 levels were significantly elevated in infectious mononucleosis. Collectively, LMP1 induces CCL17 and CCL22 in EBV-infected B cells via activation of NF-κB and probably ATF2. Production of CCL17 and CCL22, which attract Th2 and regulatory T cells, may help EBV-infected B cells evade immune surveillance by Th1 cells. However, the concomitant production of CCL3, CCL4, and CCL5 by EBV-infected B cells may eventually attract Th1 cells and cytotoxic T cells, leading to elimination of EBV-infected B cells at latency III and to selection of those with limited expression of latent genes.

scholarly journals TGF-β3-expressing CD4+CD25−LAG3+ regulatory T cells control humoral immune responses

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Tomohisa Okamura ◽  
Shuji Sumitomo ◽  
Kaoru Morita ◽  
Yukiko Iwasaki ◽  
Mariko Inoue ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Humoral Immune ◽  
Humoral Immune Responses

scholarly journals The tolerogenic interplay(s) among HLA-G, myeloid APCs, and regulatory cells

Blood ◽  
2011 ◽  
Vol 118 (25) ◽  
pp. 6499-6505 ◽  
Author(s):  
Edgardo D. Carosella ◽  
Silvia Gregori ◽  
Joel LeMaoult
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Recent Work ◽  
Large Body ◽  
Regulatory Cells ◽  
Individual Effects ◽  
The Individual ◽  
Key Aspects ◽  
Antigen Presenting

Abstract Myeloid antigen-presenting cells (APCs), regulatory cells, and the HLA-G molecule are involved in modulating immune responses and promoting tolerance. APCs are known to induce regulatory cells and to express HLA-G as well as 2 of its receptors; regulatory T cells can express and act through HLA-G; and HLA-G has been directly involved in the generation of regulatory cells. Thus, interplay(s) among HLA-G, APCs, and regulatory cells can be easily envisaged. However, despite a large body of evidence on the tolerogenic properties of HLA-G, APCs, and regulatory cells, little is known on how these tolerogenic players cooperate. In this review, we first focus on key aspects of the individual relationships between HLA-G, myeloid APCs, and regulatory cells. In its second part, we highlight recent work that gathers individual effects and demonstrates how intertwined the HLA-G/myeloid APCs/regulatory cell relationship is.

Mesenchymal stem cells induce the expansion of regulatory T cells in abortion-prone mice

Reproduction ◽  
2021 ◽  
Author(s):  
Amir Salek Farrokhi ◽  
Amir-Hassan Zarnani ◽  
Fatemeh Rezaei kahmini ◽  
Seyed Mohammad Moazzeni
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Lymph Nodes ◽  
De Novo ◽  
Abortion Rate ◽  
Cellular Mechanisms ◽  
Inguinal Lymph Nodes

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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