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1.
Commun Biol ; 5(1): 413, 2022 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-35508704

RESUMEN

Immunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans.


Asunto(s)
Estructuras Linfoides Terciarias , Animales , Quimiocinas , Ligando Coestimulador de Linfocitos T Inducibles/genética , Ligando Coestimulador de Linfocitos T Inducibles/metabolismo , Proteína Coestimuladora de Linfocitos T Inducibles/genética , Proteína Coestimuladora de Linfocitos T Inducibles/metabolismo , Inflamación , Ratones
2.
J Immunol ; 197(5): 1957-67, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27474071

RESUMEN

Lymphangiogenesis associated with tertiary lymphoid structure (TLS) has been reported in numerous studies. However, the kinetics and dynamic changes occurring to the lymphatic vascular network during TLS development have not been studied. Using a viral-induced, resolving model of TLS formation in the salivary glands of adult mice we demonstrate that the expansion of the lymphatic vascular network is tightly regulated. Lymphatic vessel expansion occurs in two distinct phases. The first wave of expansion is dependent on IL-7. The second phase, responsible for leukocyte exit from the glands, is regulated by lymphotoxin (LT)ßR signaling. These findings, while highlighting the tight regulation of the lymphatic response to inflammation, suggest that targeting the LTα1ß2/LTßR pathway in TLS-associated pathologies might impair a natural proresolving mechanism for lymphocyte exit from the tissues and account for the failure of therapeutic strategies that target these molecules in diseases such as rheumatoid arthritis.


Asunto(s)
Interleucina-7/metabolismo , Linfangiogénesis , Vasos Linfáticos/inmunología , Heterotrímero de Linfotoxina alfa1 y beta2/inmunología , Heterotrímero de Linfotoxina alfa1 y beta2/metabolismo , Estructuras Linfoides Terciarias/inmunología , Animales , Regulación de la Expresión Génica , Inflamación , Interleucina-7/genética , Interleucina-7/inmunología , Vasos Linfáticos/metabolismo , Heterotrímero de Linfotoxina alfa1 y beta2/genética , Ratones , Glándulas Salivales/inmunología , Transducción de Señal/genética , Transducción de Señal/inmunología , Estructuras Linfoides Terciarias/patología
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