RESUMO
Recent reports have provided evidence for cross-talk between regulatory T (Treg) cells and natural killer T (NKT) cells. However, it is unclear whether NKT cells play a role in the differentiation of Treg cells. By employing NKT cell-abundant Vα14 TCR transgenic (Tg) and NKT cell-deficient CD1d knock-out (KO) mice, we examined the effects of NKT cells on the in vitro differentiation of induced Treg (iTreg) cells with IL2 and TGFß. We found that iTreg induction from CD1d KO mice was significantly increased compared to the control. Also, the addition of isolated NKT cells from Vα14 TCR Tg mice to naïve CD4(+) T cells from CD1d KO mice during iTreg differentiation caused a remarkable reduction of iTreg cells. Through IFNγ neutralization, we showed that this reduction was mediated by IFNγ. Furthermore, the main source of IFNγ during iTreg differentiation was NK1.1(-)CD4(+)Foxp3(-) T cells. This finding implied that early-activated NKT cells induced Th1-type cells and subsequently underwent apoptosis. Taken together, our results suggest that NKT cells inhibit the in vitro development of iTreg cells by increasing IFNγ.
Assuntos
Interferon gama/imunologia , Ativação Linfocitária , Células T Matadoras Naturais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD1d/genética , Antígenos CD4/imunologia , Células Cultivadas , Fatores de Transcrição Forkhead/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Camundongos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T alfa-beta/genéticaRESUMO
Peripheral naive CD4(+) T cells selectively differentiate to type 1 T(h), type 2 T(h) and IL-17-producing T(h) (T(h)17) cells, depending on the priming conditions. Since these subsets develop antagonistically to each other to elicit subset-specific adaptive immune responses, balance between these subsets can regulate the susceptibility to diverse immune diseases. The present study was undertaken to determine whether poly-gamma-glutamic acid (gamma-PGA), an edible and safe exopolymer that is generated by microorganisms such as Bacillus subtilis, could modulate the development pathways of T(h) subsets. The presence of gamma-PGA during priming promoted the development of T(h)1 and T(h)17 cells but inhibited development of T(h)2 cells. gamma-PGA up-regulated the expression of T-bet and ROR-gammat, the master genes of T(h)1 and T(h)17 cells, respectively, whereas down-regulating the level of GATA-3, the master gene of T(h)2 cells. gamma-PGA induced the expression of IL-12p40, CD80 and CD86 in dendritic cells (DC) and macrophages in a Toll-like receptor-4-dependent manner, and the effect of gamma-PGA on T(h)1/T(h)2 development was dependent on the presence of antigen-presenting cells (APC). Furthermore, gamma-PGA-stimulated DC favored the polarization of naive CD4(+) T cells toward T(h)1 cells rather than T(h)2 cells. In contrast, gamma-PGA affected T(h)17 cell development, regardless of the presence or absence of APC. Thus, these data demonstrate that gamma-PGA has the potential to regulate the development pathways of naive CD4(+) T cells through APC-dependent and -independent mechanisms and to be applicable to treating T(h)2-dominated diseases.