Deletion of Irf4 in T Cells Suppressed Autoimmune Uveitis and Dysregulated Transcriptional Programs Linked to CD4+ T Cell Differentiation and Metabolism.
Int J Mol Sci
; 22(5)2021 Mar 09.
Article
en En
| MEDLINE
| ID: mdl-33803441
ABSTRACT
Interferon regulatory factor-4 (IRF4) and IRF8 regulate differentiation, growth and functions of lymphoid and myeloid cells. Targeted deletion of irf8 in T cells (CD4-IRF8KO) has been shown to exacerbate colitis and experimental autoimmune uveitis (EAU), a mouse model of human uveitis. We therefore generated mice lacking irf4 in T cells (CD4-IRF4KO) and investigated whether expression of IRF4 by T cells is also required for regulating T cells that suppress autoimmune diseases. Surprisingly, we found that CD4-IRF4KO mice are resistant to EAU. Suppression of EAU derived in part from inhibiting pathogenic responses of Th17 cells while inducing expansion of regulatory lymphocytes that secrete IL-10 and/or IL-35 in the eye and peripheral lymphoid tissues. Furthermore, CD4-IRF4KO T cells exhibit alterations in cell metabolism and are defective in the expression of two Ikaros zinc-finger (IKZF) transcription factors (Ikaros, Aiolos) that are required for lymphocyte differentiation, metabolism and cell-fate decisions. Thus, synergistic effects of IRF4 and IkZFs might induce metabolic reprogramming of differentiating lymphocytes and thereby dynamically regulate relative abundance of T and B lymphocyte subsets that mediate immunopathogenic mechanisms during uveitis. Moreover, the diametrically opposite effects of IRF4 and IRF8 during EAU suggests that intrinsic function of IRF4 in T cells might be activating proinflammatory responses while IRF8 promotes expansion of immune-suppressive mechanisms.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Autoinmunes
/
Transcripción Genética
/
Uveítis
/
Linfocitos T CD4-Positivos
/
Diferenciación Celular
/
Eliminación de Gen
/
Factores Reguladores del Interferón
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Int J Mol Sci
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos