IL-7R signaling in regulatory T cells maintains peripheral and allograft tolerance in mice

Schmaler, Mathias; Broggi, Maria A. S.; Lagarde, Nadège; Stöcklin, Benjamin; King, Catrina E.; Finke, Daniela; Rossi, Simona W.

doi:10.1073/pnas.1510045112

Cited by 37 publications

(29 citation statements)

References 48 publications

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“…They also confirm relevance in human melanoma patients, in terms of VEGF-C correlating with both T cell infiltration and response to immunotherapy, despite the well-established correlation of VEGF-C with worse prognosis in the absence of immunotherapy. Limitations of this study include uncertainty in the following: (i) the potential roles of other immune cell subsets that may be altered in VEGF-C-expressing tumors, including natural killer T cells, gd T cells, and especially various DC subsets that we found to be enriched; (ii) the extent to which numerous other cytokines that are altered in lymphangiogenic tumors contribute to immunotherapy potentiation; (iii) cell sources of VEGF-C in human tumors; and (iv) indirect effects of naïve T cell recruitment on the immune microenvironment [for example, competition with T reg cells for nutrients (44) or homeostatic cytokines such as IL-7 (45)]. These will require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma

et al. 2017

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In melanoma, vascular endothelial growth factor-C (VEGF-C) expression and consequent lymphangiogenesis correlate with metastasis and poor prognosis. VEGF-C also promotes tumor immunosuppression, suggesting that lymphangiogenesis inhibitors may be clinically useful in combination with immunotherapy. We addressed this concept in mouse melanoma models with VEGF receptor-3 (VEGFR-3)-blocking antibodies and unexpectedly found that VEGF-C signaling enhanced rather than suppressed the response to immunotherapy. We further found that this effect was mediated by VEGF-C-induced CCL21 and tumor infiltration of naïve T cells before immunotherapy because CCR7 blockade reversed the potentiating effects of VEGF-C. In human metastatic melanoma, gene expression of VEGF-C strongly correlated with CCL21 and T cell inflammation, and serum VEGF-C concentrations associated with both T cell activation and expansion after peptide vaccination and clinical response to checkpoint blockade. We propose that VEGF-C potentiates immunotherapy by attracting naïve T cells, which are locally activated upon immunotherapy-induced tumor cell killing, and that serum VEGF-C may serve as a predictive biomarker for immunotherapy response.

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Section: Discussionmentioning

confidence: 99%

Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma

et al. 2017

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“…CD25, the α-chain of the IL-2 receptor, is expressed at only intermediate/dim levels [ 1 ], questioning whether naïve-Tregs, like their memory counterparts, depend on IL-2 [ 2 ]. Moreover, Tregs per se typically express low levels of the α-chain of the IL-7 receptor (IL-7Rα), and there are controversial reports on the IL-7 impact on human and murine Tregs [ 18 - 22 ].…”

Section: Introductionmentioning

confidence: 99%

Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7

et al. 2016

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Naïve FoxP3-expressing regulatory T-cells (Tregs) are essential to control immune responses via continuous replenishment of the activated-Treg pool with thymus-committed suppressor cells. The mechanisms underlying naïve-Treg maintenance throughout life in face of the age-associated thymic involution remain unclear. We found that in adults thymectomized early in infancy the naïve-Treg pool is remarkably well preserved, in contrast to conventional naïve CD4 T-cells. Naïve-Tregs featured high levels of cycling and pro-survival markers, even in healthy individuals, and contrasted with other circulating naïve/memory CD4 T-cell subsets in terms of their strong γc-cytokine-dependent signaling, particularly in response to IL-7. Accordingly, ex-vivo stimulation of naïve-Tregs with IL-7 induced robust cytokine-dependent signaling, Bcl-2 expression, and phosphatidylinositol 3-kinase (PI3K)-dependent proliferation, whilst preserving naïve phenotype and suppressive capacity. Altogether, our data strongly implicate IL-7 in the thymus-independent long-term survival of functional naïve-Tregs, and highlight the potential of targeting the IL-7 pathway to modulate Tregs in different clinical settings.

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“…Results of recent studies in mice identified IL-7 as a necessary factor to sustain expression of high levels of CD25 at the T reg surface in vivo, thereby supporting the functional activity of effector T regs by increasing their IL-2 sensitivity [49,50].…”

Section: Discussionmentioning

confidence: 99%

STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity

Goropevšek

Gorenjak

Gradišnik

et al. 2017

Journal of Leukocyte Biology

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Activation of the STAT5 signaling pathway up-regulates antiapoptotic protein Bcl2 and drives proliferation of autoreactive conventional CD4 T cells (T). In systemic lupus erythematosus (SLE), an increased T cell Bcl2 content and perturbed homeostasis of CD45RAFOXP3 activated regulatory T cells (aT) were described. We assessed T/T subsets and phosphorylation of STAT5 (pSTAT5) in blood T cells from patients with SLE by using conventional and imaging flow cytometry. Forty-one patients with SLE, 33 healthy controls, and 29 patients with rheumatoid arthritis were included. Long-term monitoring was performed in 39 patients with SLE, which were followed longitudinally for up to 1000 d. Significantly increased Bcl2 protein content in T cells from patients with SLE was associated with IL-7-dependent STAT5 activation, expressed as increased basal levels and nuclear localization of pSTAT5. pSTAT5 levels were significantly increased in the FOXP3 low-expressing CD4 T cell subsets but not in the aT subset, which was significantly decreased in patients with SLE. In contrast to aT, SLE T displayed significantly increased pSTAT5 and Bcl2 levels. Moreover, the percentage of T-expressing proliferation marker Ki-67 was significantly increased in patients with SLE and was positively correlated with CD4 T cell pSTAT5 levels. Finally, a subgroup of patients characterized by an increased T-pSTAT5/aT-pSTAT5 ratio experienced a more aggressive-relapsing disease course and displayed higher time-adjusted cumulative CD4 T cell pSTAT5 levels during follow-up, which were positively correlated with time-adjusted cumulative disease activity. Our results indicate that imbalanced STAT5 phosphorylation, which is related to Bcl2 and Ki-67 expression, may confer survival and proliferative advantage to T over aT and could represent a possible marker of SLE disease severity.

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IL-7R signaling in regulatory T cells maintains peripheral and allograft tolerance in mice

Cited by 37 publications

References 48 publications

Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma

Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma

Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7

STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity

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