RESUMO
Interleukin-7 receptor α chain (IL-7Rα) is induced upon T cell positive selection and controls thymic CD8-lineage specification and peripheral naive T cell homeostasis. How IL-7Rα expression is regulated in developing thymocytes is unclear. Here, we show that transforming growth factor ß (TGF-ß) signaling promoted IL-7Rα expression and CD8+ T cell differentiation. In addition, TGF-ß signaling was required for high IL-7Rα expression in CD4+ T cells bearing low-affinity T cell receptors, and the abrogation of TGF-ß receptor expression led to failed maintenance of peripheral CD4+ T cells. Compromised IL-7Rα expression in TGF-ß-receptor-deficient T cells was associated with increased expression of the Il7ra transcriptional repressor, Gfi-1. IL-7Rα transgenesis or T-cell-specific ablation of Gfi-1 restored IL-7Rα expression and largely ameliorated the development and homeostasis defects of TGF-ß-receptor-deficient T cells. These findings reveal functions for TGF-ß signaling in controlling IL-7Rα expression and in promoting T cell repertoire diversification.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Receptores de Interleucina-7/metabolismo , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular , Linhagem da Célula , Proteínas de Ligação a DNA/genética , Homeostase , Camundongos , Camundongos Knockout , Proteínas Serina-Treonina Quinases/deficiência , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Antígenos de Linfócitos T , Receptores de Interleucina-7/imunologia , Receptores de Fatores de Crescimento Transformadores beta/deficiência , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Fatores de Transcrição/genéticaRESUMO
PURPOSE: To report a case of a sterile iris abscess associated with herpes zoster ophthalmicus (HZO). OBSERVATIONS: A 69-year-old African American female presented to SUNY Downstate Medical Center complaining of left-sided eye pain for two weeks. The patient had a best-corrected visual acuity of 20/30 OD and 20/200 OS. On external exam, vesicles were noted on the left upper lid and tip of the nose. Anterior segment exam was notable for decreased sensation without epithelial defects. The patient had 2+ stromal edema with 3+ cell and flare. The iris was flat with 1+ nuclear sclerosis OU. The intraocular pressure (IOP) was 14 mmHg OD and 40 mmHg OS. The patient was diagnosed with HZO with secondary uveitic glaucoma.At ten weeks, anterior segment inflammation resolved and IOP stabilized. However, an iris nodule was noted superior nasal which continued to enlarge by 16 weeks follow up. Iris ultrasound revealed a 3 × 3 mm elevated lesion with internal homogeneity suggestive of an abscess.At five months, a dense, mature cataract developed. The patient underwent cataract extraction with sector iridectomy. Gram staining and cultures were negative for organisms but positive for polymorphic neutrophils. Histopathology revealed fibrosis, surface necrosis, and stromal infiltration with chronic inflammatory cells consistent with chronic iritis and a sterile abscess secondary to HZO. CONCLUSIONS AND IMPORTANCE: HZO is associated with a range of ocular sequelae with acquired iris nodule only mentioned once in the literature. As the second documented case, our findings will add to the general fund of knowledge regarding iris lesions and HZO.
RESUMO
Peripheral T cells are maintained in the absence of vigorous stimuli, and respond to antigenic stimulation by initiating cell cycle progression and functional differentiation. Here we show that depletion of the Ets family transcription factor GA-binding protein (GABP) in T cells impairs T-cell homeostasis. In addition, GABP is critically required for antigen-stimulated T-cell responses in vitro and in vivo. Transcriptome and genome-wide GABP-binding site analyses identify GABP direct targets encoding proteins involved in cellular redox balance and DNA replication, including the Mcm replicative helicases. These findings show that GABP has a nonredundant role in the control of T-cell homeostasis and immunity.
Assuntos
Fator de Transcrição de Proteínas de Ligação GA/fisiologia , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Antígenos/imunologia , Sítios de Ligação , Antígenos CD4/genética , Proliferação de Células , Células Cultivadas , Replicação do DNA , Fator de Transcrição de Proteínas de Ligação GA/genética , Homeostase , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Manutenção de Minicromossomo/metabolismo , Linfócitos T/enzimologia , Transcrição GênicaRESUMO
Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases, including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an "alternatively activated" phenotype. TAM terminal differentiation depends on the transcriptional regulator of Notch signaling, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth. These findings reveal the ontogeny of TAMs and a discrete tumor-elicited inflammatory response, which may provide new opportunities for cancer immunotherapy.