CD4+ CD25+ Regulatory T Cells Modulate the T-Cell and Antibody Responses in Helicobacter-Infected BALB/c Mice

ABSTRACT Gastric Helicobacter spp. induce chronic gastritis that may lead to ulceration and dysplasia. The host elicits a T helper 1 (Th1) response that is fundamental to the pathogenesis of these bacteria. We analyzed immune responses in Helicobacter-infected, normal mice depleted of CD4+ CD25+ T cells to investigate the in vivo role of regulatory T cells (Tregs) in the modulation of Helicobacter immunopathology. BALB/c and transgenic mice were depleted of CD4+ CD25+ T cells by administration of an anti-CD25 antibody either at the time of infection with Helicobacter or during chronic infection and gastritis. Depletion of CD25+ Tregs prior to and during infection of mice with Helicobacter spp. did not affect either bacterial colonization or severity of gastritis. Depletion of CD25+ Tregs was associated with increased Helicobacter-specific antibody levels and an altered isotype distribution. Paragastric lymph node cells from CD25+ Treg-depleted and control infected mice showed similar proliferation to Helicobacter antigens, but only cells from anti-CD25-treated animals secreted Th2 cytokines. CD25+ Tregs do not control the level of gastritis induced by gastric Helicobacter spp. in normal, thymus-intact BALB/c mice. However, CD25+ Tregs influence the cytokine and antibody responses induced by infection. Autoimmune gastritis is not induced in Helicobacter-infected mice depleted of CD25+ Tregs but is induced in CD25+ Treg-depleted mice, which have a higher frequency of autoreactive T cells.

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CD28 disruption exacerbates inflammation in Tgf-β1-/- mice: in vivo suppression by CD4+CD25+ regulatory T cells independent of autocrine TGF-β1

Blood ◽

10.1182/blood-2003-08-2897 ◽

2004 ◽

Vol 103 (12) ◽

pp. 4594-4601 ◽

Cited By ~ 53

Author(s):

Mizuko Mamura ◽

WoonKyu Lee ◽

Timothy J. Sullivan ◽

Angelina Felici ◽

Anastasia L. Sowers ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Transforming Growth Factor ◽

Cytotoxic T Lymphocyte ◽

Tumor Necrosis Factor Receptor ◽

Transforming Growth Factor Β1 ◽

Autoimmune Inflammatory Disease ◽

Lymph Node Cells ◽

Tgf Β1

Abstract Tgf-β1-/- mice develop a progressive, lethal, inflammatory syndrome, but mechanisms leading to the spontaneous activation of Tgf-β1-/- T cells remain unclear. Here we show the disruption of CD28 gene expression accelerates disease in Tgf-β1-/- mice, and we link this increase in severity to a reduction in the number of CD4+CD25+ regulatory T cells. CD4+CD25+ T cells develop normally in Tgf-β1-/- mice and display characteristic expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), αEβ7 integrin, and Foxp3. Adoptive transfer of Tgf-β1-/- splenocytes to Tgf-β1+/+/Rag2-/- mice induced an autoimmune inflammatory disease with features similar to those of the Tgf-β1-/- phenotype, and disease transfer was accelerated by the depletion of Tgf-β1-/- CD4+CD25+ T cells from donor splenocytes. Cotransfer of Tgf- β1-/- CD4+CD25+ T cells clearly attenuated disease in Rag2-/- recipients of CD25+-depleted Tgf-β1-/- spleen and lymph node cells, but suppression was incomplete when compared with Tgf-β1+/+ CD4+CD25+ T cells. These data demonstrate that CD4+CD25+ regulatory T cells develop in complete absence of endogenous transforming growth factor-β1 (TGF-β1) expression and that autocrine TGF-β1 expression is not essential for these cells to suppress inflammation in vivo. (Blood. 2004;103:4594-4601)

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

Blood ◽

10.1182/blood.v110.11.1160.1160 ◽

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.

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