RESUMO
TGF-ß type III receptor (TßRIII) is a co-receptor for TGFß family members required for high-affinity binding of these ligands to their receptors, potentiating their cellular functions. TGF-ßs, Bone Morphogenetic Proteins (BMP2/4) and Inhibins/Activins regulate different checkpoints during T cell differentiation. We have previously reported that TßRIII modulates T cell development by protecting developing thymocytes from apoptosis, however the role of this co-receptor in peripheral lymphocytes still remains elusive. Here we describe a detailed characterization of TßRIII expression in murine and human lymphocyte subpopulations demonstrating that this co-receptor is significantly expressed in T but not B lymphocytes and among them, preferentially expressed on naïve and central memory T cells. TßRIII was upregulated after TCR stimulation, in parallel to other early activation markers. In contrast, natural and induced Tregs downregulated TßRIII in association with FoxP3 upregulation. Finally, anti-TßRIII blocking experiments demonstrated that TßRIII promotes TGFß-dependent iTreg conversion in vitro, and suggest that this co-receptor may be involved in modulating peripheral T cell tolerance and could be considered as a potential target to boost T cell immune responses.
Assuntos
Proteoglicanas/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Regulação para Baixo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Memória Imunológica , Técnicas In Vitro , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteoglicanas/antagonistas & inibidores , Proteoglicanas/genética , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais , Linfócitos T Reguladores/classificação , Linfócitos T Reguladores/metabolismo , Regulação para CimaRESUMO
Inhibins and Activins are members of the TGF-ß superfamily that regulate the differentiation of several cell types. These ligands were initially identified as hormones that regulate the hypothalamus-pituitary-gonadal axis; however, increasing evidence has demonstrated that they are key regulators in the immune system. We have previously demonstrated that Inhibins are the main Activin ligands expressed in the murine thymus and that they regulate thymocyte differentiation, promoting the DN3-DN4 transition and the selection of SP thymocytes. As Inhibins are mainly produced by thymic stromal cells, which also express Activin receptors and Smad proteins, we hypothesized that Inhibins might play a role in stromal cell differentiation and function. Here, we demonstrate that, in the absence of Inhibins, thymic conventional dendritic cells display reduced levels of MHC Class II (MHCII) and CD86. In addition, the ratio between cTECs and mTECs was affected, indicating that mTEC differentiation was favoured and cTEC diminished in the absence of Inhibins. These changes appeared to impact thymocyte selection leading to a decreased selection of CD4SP thymocytes and increased generation of natural regulatory T cells. These findings demonstrate that Inhibins tune the T cell selection process by regulating both thymocyte and stromal cell differentiation.