Activated CD1d‐restricted natural killer T cells secrete IL‐2: innate help for CD4<sup>+</sup>CD25<sup>+</sup> regulatory T cells?

Jiang, Shuiping; Game, David; Davies, Derek; Lombardi, Giovanna; Lechler, Robert I.

doi:10.1002/eji.200425899

Cited by 82 publications

(74 citation statements)

References 30 publications

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“…These different results could be accounted for if another CD1d-restricted NKT cell population, different from the typanosome-controlling CD8 ϩ NKT cells, is contributing to expansion of Tregs. In fact, a subset of CD4 ϩ NKT cells, but not CD4 Ϫ NKT cells, has been reported to secrete abundant IL-2 that, in turn, promotes proliferation of Tregs (32). Thus, we conclude that the anti-CD8-treated wt mice lack a CD8 ϩ NKT cell population that induces early control of the trypanosomes but has a CD8 Ϫ NKT cell population that contributes to the expansion of Tregs.…”

Section: Discussionmentioning

confidence: 70%

Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

Wei

Tabel

2008

The Journal of Immunology

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African trypanosomes are single-cell, extra-cellular blood parasites causing profound immunosuppression. Susceptible BALB/c mice infected s.c. into a footpad with 104 Trypanosoma congolense die with fulminating parasitemia within 10 days. We injected BALB/c mice 2 days before such an infection with different doses of a depleting mAb specific for CD25, a surface marker of regulatory T cells (Tregs). Pretreatment with a low, optimal dose of anti-CD25 resulted in a dramatic effect, in that the infected mice did not develop parasitemia, as well as eliminated all parasites and showed no signs of disease. Their spleens showed a 100% reduction of CD4+CD25high T cells and overall a 70% reduction of CD4+CD25+Foxp3+ T cells 7 days postinfection. The protective effect of treatment with an optimal dose of anti-CD25 could be reversed by administration of l-N6-(1-imminoethyl) lysine, a specific inhibitor of inducible NO synthase or administration of anti-CD8 Ab. Analysis of the cytokine patterns and cell surface marker in infected mice pretreated with anti-CD25 Abs pointed to a potential NKT cell response. We then conducted infections in CD1d−/− mice. From our observations, we conclude that CD4+CD25highFoxp3+ Tregs prevent, in normal infected susceptible mice, an early protective response mediated by CD8+ NKT cell-dependent activation of macrophages to kill parasites by production of NO. Our results also indicate that different populations of NKT cells have protective or suppressive effects. Our observations lead us to propose a hypothesis of cross-regulation of NKT cells and Tregs in trypanosome infections.

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Section: Discussionmentioning

confidence: 70%

Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

Wei

Tabel

2008

The Journal of Immunology

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“…iNKT cells can also act as effector cells, namely via their IL-17-producing subset, which enhances lung inflammatory responses (10,20). In addition to their ability to amplify the immune response in various ways, iNKT cells can likewise contribute to the negative control of the immune system by promoting regulatory T (Treg) cell expansion through their secretion of IL-2 (21). Foxp3 expression at protein or mRNA levels by mouse and human iNKT cells was already described (22,23).…”

Section: Nvariant Nkt (Inkt) Cells Have Elicited Considerable Intermentioning

confidence: 96%

Rapamycin Combined with TGF-β Converts Human Invariant NKT Cells into Suppressive Foxp3+ Regulatory Cells

Moreira-Teixeira

Resende

Devergne

et al. 2012

The Journal of Immunology

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Invariant NKT (iNKT) cells constitute a versatile T cell subset with important regulatory functions, which are thought to result essentially from their capacity to promptly produce cytokines that influence the Th1/Th2 balance. In this study, we report that these cells can also express Foxp3, an important transcriptional regulator associated with suppressive activity, once they have been exposed to TGF-β. Foxp3 was expressed by iNKT cells from both peripheral and cord blood. CD4+ iNKT cells acquired Foxp3 expression preferentially, although a lower proportion of their CD4− counterpart also became positive. All Foxp3+ iNKT cells displayed CD25 but not necessarily CTLA4 or GITR, regardless of the upregulation of these markers in the presence of TGF-β. Exposure to TGF-β decreased IL-4 and IFN-γ production while increasing IL-10, independently from Foxp3 expression. IL-17 was not detected. TGF-β induced high levels of Foxp3, but no suppressor activity, which emerged only in the presence of rapamycin. Peripheral and cord blood Foxp3+ iNKT cells suppressed the proliferation of conventional autologous and heterologous CD4+ T cells equally, in a cell contact-dependent and Ag-independent manner. Our findings demonstrate that human iNKT cells become suppressive in the presence of TGF-β plus rapamycin, thus adding a new facet to their complex functional properties.

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“…In humans, 'classical' type I iNK T co-express the invariant TCR Va24-Ja18 and Vb11 chains [11], and these cells have been shown to be required in the induction of long-term allograft tolerance [12]. Several recent reports have described a cross-regulation between Treg and iNK T [13,14], both subsets therefore having been shown to be important for allograft tolerance induction [15,16], possibly in a co-ordinated fashion.…”

Section: Cd8mentioning

confidence: 99%

“…Several recent publications have described crossregulation between Treg and iNK T cells. iNK T cells modulate the Treg functions quantitatively and qualitatively through IL-2, IL-4 and IL-10-dependent mechanisms, whereas Treg can suppress the proliferation, cytokine release and cytotoxic activity of iNK T cells by cell contactdependent mechanisms [13,14]. The existence of an IL-10 and IL-4-dependent immune regulatory interplay among iNK T cells, dendritic cells and CD4 Treg has been shown in animal models of allogenic cardiac and bone marrow transplantation, demonstrating the importance of this crossregulation in allograft tolerance induction [15,16].…”

Section: Treg and Inkt Cells In Allograft Recipientsmentioning

confidence: 99%

Reduced levels of both circulating CD4+CD25+CD127low/neg and CD4+CD8neg invariant natural killer regulatory T cells in stable heart transplant recipients

Chen

Mohtize

Mattei

et al. 2010

Clinical and Experimental Immunology

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SummaryA cross-regulation between two regulatory T cell (Treg) subsets [CD4 + CD25 + and invariant natural killer (NK) T -iNK T] has been described to be important for allograft tolerance induction. However, few studies have evaluated these cellular subsets in stable recipients as correlates of favourable clinical outcome after heart transplantation. Treg and iNK T cell levels were assayed by flow cytometry in peripheral blood samples from 44 heart transplant recipients at a 2-year interval in 38 patients, and related to clinical outcome. Multiparameter flow cytometry used CD4/CD25/CD127 labelling to best identify Treg, and a standard CD3/CD4/CD8/Va24/Vb11 labelling strategy to appreciate the proportions of iNK T cells. Both subtypes of potentially tolerogenic cells were found to be decreased in stable heart transplant recipients, with similar or further decreased levels after 2 years. Interestingly, the patient who presented with several rejection-suggesting incidents over this period displayed a greater than twofold increase of both cell subsets. These results suggest that CD4 + CD25 + CD127 low/neg Treg and iNK T cells could be involved in the local control of organ rejection, by modulating immune responses in situ, in clinically stable patients. The measurement of these cell subsets in peripheral blood could be useful for non-invasive monitoring of heart transplant recipients, especially in the growing context of tolerance-induction trials.

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Activated CD1d‐restricted natural killer T cells secrete IL‐2: innate help for CD4⁺CD25⁺ regulatory T cells?

Cited by 82 publications

References 30 publications

Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

Rapamycin Combined with TGF-β Converts Human Invariant NKT Cells into Suppressive Foxp3+ Regulatory Cells

Reduced levels of both circulating CD4+CD25+CD127low/neg and CD4+CD8neg invariant natural killer regulatory T cells in stable heart transplant recipients

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Activated CD1d‐restricted natural killer T cells secrete IL‐2: innate help for CD4+CD25+ regulatory T cells?

Cited by 82 publications

References 30 publications

Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

Regulatory T Cells Prevent Control of Experimental African Trypanosomiasis

Rapamycin Combined with TGF-β Converts Human Invariant NKT Cells into Suppressive Foxp3+ Regulatory Cells

Reduced levels of both circulating CD4+CD25+CD127low/neg and CD4+CD8neg invariant natural killer regulatory T cells in stable heart transplant recipients

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Activated CD1d‐restricted natural killer T cells secrete IL‐2: innate help for CD4⁺CD25⁺ regulatory T cells?