A Crucial Role of RORγt in the Development of Spontaneous Sialadenitis-like Sjögren’s Syndrome

Abstract

The nuclear receptor retinoic acid–related orphan receptor (ROR)γt is required for the generation of Th17 cells, which are involved in various autoimmune diseases, including Sjögren’s syndrome (SS). However, the pathological role of RORγt in SS remains to be elucidated. The present study was designed to clarify the role of RORγt in the pathogenesis of sialadenitis-like SS. Histological analysis of RORγt transgenic (Tg) mice was determined, and then Tg mice developed severe spontaneous sialadenitis-like SS. The analysis of infiltrating cells showed that most infiltrating cells were CD4+ T cells. RORγt-overexpressing CD4+ T cells induced sialadenitis as a result of transferred CD4+ T cells from Tg mice into Rag2−/− mice. The examination of IL-17–deficient Tg mice indicated that IL-17 was not essential for the development of sialadenitis. The number of CD4+CD25+Foxp3+ regulatory T (Treg) cells was significantly decreased in Tg mice, and CD25 expression and IL-2 stimulated STAT5 activation were inhibited in Treg cells. The inhibitory function of Treg cells of Tg mice was equal to that of wild-type mice in vitro. The abundant Treg cells of Tg mice could suppress the development of sialadenitis, but the reduced Treg cells of Tg mice could not inhibit the induction of sialadenitis in Rag2−/− mice transferred with effector cells from Tg mice. These results suggest that both RORγt-overexpressed CD4+ T cells and reduced Treg cells might contribute to the development of SS-like sialadenitis.

New Murine Model of Early Onset Autoimmune Thyroid Disease/Hypothyroidism and Autoimmune Exocrinopathy of the Salivary Gland

“…They were fixed in formalin, sectioned and stained with H&E. The extent of lymphocyte infiltration inthe salivary glands was scored by counting the number of foci/lymphocyte aggregates consisting of >50 lymphocytes (9, 21, 22). All scoring was done in a blinded manner using the microscope and MetaMorph software indicated below.…”

“…All scoring was done in a blinded manner using the microscope and MetaMorph software indicated below. Focus scores are defined as the number of lymphocyte foci (>50 cells) per 4mm 2 of tissue (22). Images of whole submandibular gland sections were generated by stitching together multiple 40X magnification images using a Zeiss Axiovert 200M microscope and MetaMorph software at the University of Missouri Molecular Cytology Core Facility.…”

RORγt antagonist improves Sjögren's syndrome‐like sialadenitis through downregulation of CD25

“…The nuclear receptor retinoic acid‐related orphan receptor t (RORγt) plays an indispensable role in the differentiation of Th17 cells (Ivanov et al, ; Ivanov, Zhou, & Littman, ; Manel, Unutmaz, & Littman, ; Yang et al, ). We showed previously that T‐cell‐specific RORγt‐transgenic mice under human CD2 promoter (RORγt‐Tg mice) developed severe spontaneous SS‐like sialadenitis and that RORγt‐overexpressing CD4 + T cells and reduction of Treg cells contributed to the development of SS‐like sialadenitis in these mice (Iizuka, Tsuboi, Asashima, et al, ; Iizuka, Tsuboi, Matsuo, et al, ). RORγt‐overexpressing CD4 + T cells include various T‐cell subsets, such as Th1, Th2, Th17, and T follicular helper (Tfh) cells, and are known to produce IFNγ, IL‐4, IL‐17, and IL‐21, which play significant roles in the immunopathogenesis in RORγt‐Tg mice (Iizuka, Tsuboi, Asashima, et al, ; Iizuka, Tsuboi, Matsuo, et al, ).…”

“…We showed previously that T‐cell‐specific RORγt‐transgenic mice under human CD2 promoter (RORγt‐Tg mice) developed severe spontaneous SS‐like sialadenitis and that RORγt‐overexpressing CD4 + T cells and reduction of Treg cells contributed to the development of SS‐like sialadenitis in these mice (Iizuka, Tsuboi, Asashima, et al, ; Iizuka, Tsuboi, Matsuo, et al, ). RORγt‐overexpressing CD4 + T cells include various T‐cell subsets, such as Th1, Th2, Th17, and T follicular helper (Tfh) cells, and are known to produce IFNγ, IL‐4, IL‐17, and IL‐21, which play significant roles in the immunopathogenesis in RORγt‐Tg mice (Iizuka, Tsuboi, Asashima, et al, ; Iizuka, Tsuboi, Matsuo, et al, ). Surprisingly, IL‐17 was not essential for the development of sialadenitis in this model (Iizuka, Tsuboi, Asashima, et al, ; Iizuka, Tsuboi, Matsuo, et al, ).…”

“…RORγt‐overexpressing CD4 + T cells include various T‐cell subsets, such as Th1, Th2, Th17, and T follicular helper (Tfh) cells, and are known to produce IFNγ, IL‐4, IL‐17, and IL‐21, which play significant roles in the immunopathogenesis in RORγt‐Tg mice (Iizuka, Tsuboi, Asashima, et al, ; Iizuka, Tsuboi, Matsuo, et al, ). Surprisingly, IL‐17 was not essential for the development of sialadenitis in this model (Iizuka, Tsuboi, Asashima, et al, ; Iizuka, Tsuboi, Matsuo, et al, ).…”