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1.
Cell ; 184(26): 6281-6298.e23, 2021 12 22.
Artículo en Inglés | MEDLINE | ID: mdl-34875227

RESUMEN

While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1+ IL-17+ SLAMF6+ population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF+ IFN-γ+ CXCR6+ T cells. Our study defines a direct in vivo relationship between IL-17+ non-pathogenic and GM-CSF+ and IFN-γ+ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.


Asunto(s)
Autoinmunidad , Intestinos/inmunología , Células Madre/metabolismo , Células Th17/inmunología , Animales , Movimiento Celular , Células Clonales , Encefalomielitis Autoinmune Experimental/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Homeostasis , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Especificidad de Órganos , ARN/metabolismo , RNA-Seq , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CXCR6/metabolismo , Receptores de Interleucina/metabolismo , Reproducibilidad de los Resultados , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Análisis de la Célula Individual , Bazo/metabolismo
2.
Nat Immunol ; 24(11): 1908-1920, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37828379

RESUMEN

Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Neoplasias , Animales , Humanos , Ratones , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/genética , Inmunoterapia , Inflamación , Enfermedades Neuroinflamatorias , Microambiente Tumoral
3.
Immunity ; 55(9): 1663-1679.e6, 2022 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-36070768

RESUMEN

Interleukin-23 receptor plays a critical role in inducing inflammation and autoimmunity. Here, we report that Th1-like cells differentiated in vitro with IL-12 + IL-21 showed similar IL-23R expression to that of pathogenic Th17 cells using eGFP reporter mice. Fate mapping established that these cells did not transition through a Th17 cell state prior to becoming Th1-like cells, and we observed their emergence in vivo in the T cell adoptive transfer colitis model. Using IL-23R-deficient Th1-like cells, we demonstrated that IL-23R was required for the development of a highly colitogenic phenotype. Single-cell RNA sequencing analysis of intestinal T cells identified IL-23R-dependent genes in Th1-like cells that differed from those expressed in Th17 cells. The perturbation of one of these regulators (CD160) in Th1-like cells inhibited the induction of colitis. We thus uncouple IL-23R as a purely Th17 cell-specific factor and implicate IL-23R signaling as a pathogenic driver in Th1-like cells inducing tissue inflammation.


Asunto(s)
Colitis , Receptores de Interleucina , Animales , Inflamación/metabolismo , Interleucina-23/metabolismo , Ratones , Ratones Endogámicos C57BL , Fenotipo , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Células TH1 , Células Th17
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