Human CD4+CD25+ Regulatory, Contact-dependent T Cells Induce Interleukin 10–producing, Contact-independent Type 1-like Regulatory T Cells

Dieckmann, Detlef; Bruett, Cord Henrik; Ploettner, Heidi; Lutz, Manfred B.; Schuler, Gerold

doi:10.1084/jem.20020642

Cited by 424 publications

(359 citation statements)

References 31 publications

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“…Mice deficient in IL-10 develop severe inflammatory bowel disease [31][32][33] and IL-10 is important in oral tolerance development [34][35][36]. Noteworthy from this view is that GF animals are less prone to oral tolerization [37][38][39][40][41], and CD4 + CD25 + cells transferred from gnotobiotic mice show only an intermediate protection in a colitis model induced by the transfer of naive T cells depleted of regulatory cells [42].…”

Section: Discussionmentioning

confidence: 99%

Impaired regulatory T cell function in germ‐free mice

et al. 2006

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Regulatory T cells (Treg) are crucial for the maintenance of tolerance to auto-antigens and harmless exogenous antigens. Here, we studied the role of the commensal microbiota for the development and function of Treg. CD4 + CD25 + T cells were obtained from peripheral lymph nodes (PLN) and mesenteric lymph nodes (MLN) of germ-free (GF) and conventional (conv) NMRI mice and tested for phenotype and functional suppressive capacity. CD4 + CD25 + T cells from GF mice showed a lower relative gene expression of fork head box p3 gene (Foxp3) and were not as potent suppressors in vitro as CD4 + CD25 + T cells from conv animals. Intracellular staining for Foxp3 and CTLA-4 revealed proportional and regional differences in putative Treg subsets between conv and GF mice. Fewer of the CD4 + CD25 + T cells in GF MLN expressed Foxp3 and CTLA-4, while the expression of these markers was similar amongst the CD4 + CD25 + T cells in PLN of conv and GF mice. The largest difference between conv and GF Treg was observed in the liver draining celiac lymph node, where GF mice had fewer putative Treg as compared to conv mice. We propose that the presence of a microbial flora favors the development of a fully functional Treg population. IntroductionRegulatory T cells down-regulate unwanted and exaggerated immune reactions to auto-antigens as well as innocuous environmental antigens. Different subsets of Treg have been defined. Natural CD4 + CD25 + Treg are positively selected for tissue-specific self-Ag in the thymus and exert their suppressive effect by cell-cell contact-dependent mechanisms [1]. Deficiency in the Treg population or neonatal thymectomy result in multiorgan autoimmune diseases [2][3][4][5][6][7][8]. Treg are characterized by a dense surface expression of CD25 (the a-chain of the IL-2-receptor), glucocorticoidinduced TNF receptor (GITR) and intracellular CTLA-4, however, these markers may be present on activated T cells. CD4 + CD25 + Tregs appear to be unique in transcribing the fork head box p3 gene (Foxp3) transcription factor [6,9], which enable their identification either with PCR are or newly developed mAb to the Foxp3 protein. Lack of a functional Foxp3 gene result in the severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), characterized by organ-specific autoimmunity, colitis and high IgE levels [10,11]. Mice with spontaneous or induced mutations in the Foxp3 gene that impair Foxp3 expression fail to develop CD4 + CD25 + Treg and exhibit a syndrome similar to IPEX [5,6].Other subsets of Treg are induced in the periphery and are referred to as Th3 [12][13][14] and Tr1 cells [15][16][17][18][19] can also generate Treg. This implies that the state of the APC and the local cytokine milieu, e.g. in the normal gut where both IL-10 and TGF-b are abundant, can determine the outcome of an immune reaction, and that Treg are induced under these circumstances.The aim of this study was to investigate the phenotype and functionality of CD4 + CD25 + Treg from germ-free (GF) ...

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Section: Discussionmentioning

confidence: 99%

Impaired regulatory T cell function in germ‐free mice

et al. 2006

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“…These observations indicated that T regs play important roles in immunological homeostasis. Although the mechanisms of suppression by T regs are still unclear, it has been reported that T regs can inhibit the function of effector T cells directly through cell-to-cell contact or indirectly via the secretion of immune-suppressive cytokines, and also suppress the Agpresenting function of dendritic or NK cells (Dieckmann et al, 2002;Misra et al, 2004;Earle et al, 2005;Longhi et al, 2006;Smyth et al, 2006).…”

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confidence: 99%

Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer

et al. 2007

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It has been reported that the population of regulatory T cells (T regs) is increased in tumour-infiltrating lymphocytes in cancer-bearing hosts. Recently, forkhead/winged helix transcription factor p3, Foxp3, is thought to be the most reliable marker of T regs. In the present study, we investigated the prevalence and localisation pattern of Foxp3 þ cells in gastric cancer (n ¼ 80) by immunohistochemistry, in relation to the clinical outcome of gastric cancer patients. Immunohistochemical staining was performed with anti-Foxp3 mAb, and Foxp3 þ cells were semiquantified. We divided all cases into two groups: Foxp3 þ -high (n ¼ 40) and Foxp3 þ -low (n ¼ 40) groups, by the median size of the population of Foxp3 þ cells. Furthermore, in terms of the localisation pattern of accumulating Foxp3 þ cells in tumours, we classified all cases into three groups: a peri-tumour group (n ¼ 30), a diffuse group (n ¼ 40), and a follicular group (n ¼ 10). As a result, although the populations of Foxp3 þ cells in stage IV were significantly larger than those in stage I (Po0.05), there was no significant difference in survival between the patients with high and low population levels of Foxp3 þ cells. However, survival in patients with a diffuse pattern of Foxp3 þ cells was significantly poorer than in those with a peritumoral pattern. In conclusion, the localisation pattern, but not the population size, of Foxp3 þ cells was significantly related to patient survival.

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“…The acquisition of antigen-specific regulatory functions by CD25 -T cells in tolerant animals could reveal an education [44,45] of conventional alloreactive CD25 -T cells by "natural" regulatory CD25 + T cells [37,38]. This hypothesis has to be reconciled with the apparent absence of expansion of the regulatory CD25 + T cell pool in tolerant recipients.…”

Section: Discussionmentioning

confidence: 99%

“…In mice and rats, regulatory CD25 + T cells have been shown to control host anti-graft responses in recipients tolerant to skin allografts following multiple pretransplant donor-specific transfusions [20,27]. CD25 - The acquisition of antigen-specific regulatory functions by CD25 -T cells in tolerant animals could reveal an education [44,45] of conventional alloreactive CD25 -T cells by "natural" regulatory CD25 + T cells [37,38]. This hypothesis has to be reconciled with the apparent absence of expansion of the regulatory CD25 + T cell pool in tolerant recipients.…”

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confidence: 99%

Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

et al. 2006

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Donor-specific heart allograft acceptance can be induced in the MHC-mismatched LEW.1 W to LEW.1A rat by donor-specific transfusions. Whereas the induction phase of tolerance has been studied in detail, its maintenance remained poorly understood. Here, we performed a side-by-side comparison of CD25 + and CD25 -splenic T cells of 100-day tolerant rats. Administration of CD25 -T cells from tolerant rats to sublethally irradiated recipients transferred long-term graft survival. These CD25 -T cells displayed a decreased donor-specific response in the mixed lymphocyte reaction and presented suppressive activity. These CD25 -T cells accumulated IFN-c, IL-10 and Foxp3 transcripts. The in vitro suppressive activity of CD25 -T cells required both cell contact and soluble factors (IL-10 and IFN-c). The CD25 + T cells from tolerant rats did not show any modification of their regulatory properties. We show that splenic CD25 -T cells of tolerant rats contribute to the maintenance of tolerance following the transplantation. Our data show that regulatory T cells are not restricted to the CD4 + CD25 + T cell subset and provide new insights on the mechanisms of tolerance to allograft following donor cell priming. IntroductionInduction of specific tolerance for donor antigens (see [1] for review) is one of the most actively explored fields in transplantation immunology. Donor-specific blood transfusion (DST) is a clinically and experimentally proven method to induce hyporesponsiveness and does not necessarily require additional immunotherapy [2][3][4][5][6]. However, the use of DST clinically has become less popular with the advent of calcineurin inhibitors and because a clear understanding of the mechanisms involved had remained elusive [4,6].In adult rats, long-term survival of MHC-incompatible vascularized allografts (heart or kidney) can be obtained by priming the recipients with donor blood cells [7,8]. We and others have shown that inhibition of early allograft rejection by DST mostly affects helper T cell functions [9][10][11] and requires intact resident dendritic cells at the time of transplantation [12]. Early production of and differentiation of CD8 + clonal regulatory cells [14][15][16] are also involved. DST treatment results in a complex state where symptoms of chronic graft rejection coexist [17] with mechanisms controlling the host acute anti-donor immune response. Long-term recipients accept a donor-derived skin graft whereas a third-party graft is rejected [17]. Moreover, the spleen [18], and possibly the graft itself [19], * These authors contributed equally to this paper. ** These authors contributed equally to this paper. harbors donor-specific regulatory T cells able to protect naive recipients from allogeneic heart rejection. Therefore, the immunological status of allograft recipients following DST pre-conditioning provides another example of the differentiation of regulatory cells described in mice [20][21][22][23] or in rats [18,24] following different "tolerance" induction maneuvers (see [25] for review)...

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Human CD4+CD25+ Regulatory, Contact-dependent T Cells Induce Interleukin 10–producing, Contact-independent Type 1-like Regulatory T Cells

Cited by 424 publications

References 31 publications

Impaired regulatory T cell function in germ‐free mice

Impaired regulatory T cell function in germ‐free mice

Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer

Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

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Human CD4+CD25+ Regulatory, Contact-dependent T Cells Induce Interleukin 10–producing, Contact-independent Type 1-like Regulatory T Cells

Cited by 424 publications

References 31 publications

Impaired regulatory T cell function in germ‐free mice

Impaired regulatory T cell function in germ‐free mice

Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer

Development of CD25– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival

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Development of CD25^– regulatory T cells following heart transplantation: Evidence for transfer of long‐term survival