Melanoma is one of the most aggressive cancers, and its incidence is increasing. These tumors derive from the melanocyte lineage and remain incurable after metastasis. Here we report that SONIC HEDGEHOG (SHH)-GLI signaling is active in the matrix of human hair follicles, and that it is required for the normal proliferation of human melanocytes in culture. SHH-GLI signaling also regulates the proliferation and survival of human melanomas: the growth, recurrence, and metastasis of melanoma xenografts in mice are prevented by local or systemic interference of HH-GLI function. Moreover, we show that oncogenic RAS-induced melanomas in transgenic mice express Gli1 and require Hh-Gli signaling in vitro and in vivo . Finally, we provide evidence that endogenous RAS-MEK and AKT signaling regulate the nuclear localization and transcriptional activity of GLI1 in melanoma and other cancer cells. Our data uncover an unsuspected role of HH-GLI signaling in melanocytes and melanomas, demonstrate a role for this pathway in RAS-induced tumors, suggest a general integration of the RAS/AKT and HH-GLI pathways, and open a therapeutic approach for human melanomas.

Objective: Regulatory T cells (Tregs) play an important role in infections modulating host immune responses and avoiding overreactive immunity. The mechanisms underlying their action in HIV-infected patients have not been well established. HIV can infect Treg, but little is known about the effects of the infection on Treg phenotype and function. The objective of this study was to investigate whether in-vitro HIV infection modifies the phenotype and suppressive capacity of Treg cells. Design: Because Treg cells are a subset of CD4⁺ T cells, HIV infection could produce alterations in the phenotype and methylation pattern of Treg disturbing the functionality of these cells. Methods: Isolated Treg cells from healthy volunteers were cultured in the presence of HIV-1, and phenotype, methylation pattern of FOXP3 locus, cytokine secretion profile and suppressive function of infected Treg were analysed in comparison with noninfected Treg. Results: We demonstrate that HIV-1 directly infects Treg and deregulates the function and the phenotype that define these cells. HIV infection downregulates the Foxp3 expression in Treg, which is followed by the loss of suppressive capacity and alterations in cytokine secretion pattern, with decreased production of transforming growth factor-beta (TGF-β) and an increased production of interleukin (IL)-4. Foxp3 downregulation in HIV-infected Treg was related to an increase in the expression of DNA methyltransferase3b (DNMT3b) associated with higher methylation of CpG sites in the FOXP3 locus. Conclusion: These findings are pivotal to our understanding of the role of Treg in HIV infection and indicate that regulatory function could be seriously impaired in HIV-infected patients contributing to the immune hyperactivation.

Due to their suppressive capacity, regulatory T cells (Tregs) have attracted growing interest as an adoptive cellular therapy for the prevention of allograft rejection, but limited Treg recovery and lower quality of adult-derived Tregs could represent an obstacle to success. To address this challenge, we developed a new approach that provides large quantities of Tregs with high purity and excellent features, sourced from thymic tissue routinely removed during pediatric cardiac surgeries (thyTregs). We report on a 2-year follow-up of the first patient treated worldwide with thyTregs, included in a phase I/II clinical trial evaluating the administration of autologous thyTreg in infants undergoing heart transplantation. In addition to observing no adverse effects that could be attributed to thyTreg administration, we report that the Treg frequency in the periphery was preserved during the 2-year follow-up period. These initial results are consistent with the trial objective, which is to confirm safety of the autologous thyTreg administration and its capacity to restore the Treg pool.

Regulatory T cells (Treg) play an important role in infections, by modulating host immune responses and avoiding the over-reactive immunity that in the case of HIV infection leads to a marked erosion and deregulation of the entire immune system. Therefore, the suppressive function of Treg in HIV-infected patients is critical because of their implication on preventing the immune hyperactivation, even though it could also have a detrimental effect by suppressing HIV specific immune responses. In recent years, several studies have shown that HIV-1 can directly infect Treg, disturbing their phenotype and suppressive capacity via different mechanisms. These effects include Foxp3 and CD25 downregulation, and the impairment of suppressive capacity. This review describes the functional mechanisms of Treg to modulate immune activation during HIV infection, and how such control is no longer fine-tune orchestrated once Treg itself get infected. We will review the current knowledge about the HIV effects on the Treg cytokine expression, on pathways implying the participation of different ectoenzymes (i.e. CD39/CD73 axis), transcription factors (ICER), and lastly on cAMP, one of the keystones in Treg suppressive function. To define which are the HIV effects upon these regulatory mechanisms is not only crucial for the comprehension of immune deregulation in HIV-infected patients but also for the correct understanding of the role of Treg cells in HIV infection.