Abstract
Several mechanisms of immune suppression have been attributed to Foxp3+ T regulatory cells (Treg) including modulation of target cells via inhibition of cell proliferation, alteration of cytokine secretion, and modification of cell phenotype, among others. Neuropilin-1 (Nrp1), a co-receptor protein highly expressed on Treg cells has been involved in tolerance-mediated responses, driving tumor growth and transplant acceptance. Here, we extend our previous findings showing that, despite expressing Foxp3, Nrp1KO Treg cells have deficient suppressive function in vitro in a contact-independent manner. In vivo, the presence of Nrp1 on Treg cells is required for driving long-term transplant tolerance. Interestingly, Nrp1 expression on Treg cells was also necessary for conventional CD4+ T cells (convT) to become Nrp1+Eos+ T cells in vivo. Furthermore, adoptive transfer experiments showed that the disruption of Nrp1 expression on Treg cells not only reduced IL-10 production on Treg cells, but also increased the frequency of IFNγ+ Treg cells. Similarly, the presence of Nrp1KO Treg cells facilitated the occurrence of IFNγ+CD4+ T cells. Interestingly, we proved that Nrp1KO Treg cells are also defective in IL-10 production, which correlates with deficient Nrp1 upregulation by convT cells. Altogether, these findings demonstrate the direct role of Nrp1 on Treg cells during the induction of transplantation tolerance, impacting indirectly the phenotype and function of conventional CD4+ T cells.
Highlights
Foxp3+ T regulatory (Treg) cells are an important population of leukocytes that control immunity, mainly by dampening effector T cell responses
In the case of convT cells, we find a partial decrease in Nrp1 expression only in the Spl, which could correspond to antigen experienced ex-Treg cells (Foxp3-T cells), since convT cells were considered and gated as Foxp3-cells
Nrp1 has been previously proposed as a cell marker for thymic-derived Treg cells [39]; but its expression has been described on T cells during allogeneic skin graft rejection [22], sepsis [40], IL-10 deficiency [41], and anti-tumor immune responses [42, 43]
Summary
Foxp3+ T regulatory (Treg) cells are an important population of leukocytes that control immunity, mainly by dampening effector T cell responses. Many studies have described the mechanisms by which Treg cells carry out their function, such as IL-2 deprivation, secretion of cytotoxic granules (granzyme/perforin), metabolic disruption, secretion of anti-inflammatory cytokines, and release of extracellular vesicles (exosomes) [1, 2]. In addition to their capacity to suppress immune responses, Treg cells had become an interesting target for cell therapy, due to the increasing number of diseases associated with malfunction and Neuropilin-1 and Modulation of T Cells over-reactivity of the immune system, such as autoimmunity and transplant rejection [3, 4]. Understanding Treg cell biology and its mechanisms of immune suppression may improve the potential and use of Treg cells as therapeutic agents
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