Impaired antigen-specific lymphocyte priming in mice after Toll-like receptor 4 activation via induction of monocytic myeloid-derived suppressor cells.
Eur J Immunol
; 49(4): 546-563, 2019 04.
Article
en En
| MEDLINE
| ID: mdl-30671932
ABSTRACT
In sepsis, the pathology involves a shift from a proinflammatory state toward an immunosuppressive phase. We previously showed that an agonistic anti-TLR4 antibody induced long-term endotoxin tolerance and suppressed antigen-specific secondary IgG production when primed prior to immunization with antigen. These findings led us to speculate that TLR4-induced innate tolerance due to primary infection causes an immunosuppressive pathology in sepsis. Therefore, the mechanism underlying impaired antigen-specific humoral immunity by the TLR4 antibody was investigated. We showed, in a mouse model, that primary antigen-specific IgG responses were impaired in TLR4 antibody-induced tolerized mice, which was the result of reduced numbers of antigen-specific GC B cells and plasma cells. Ovalbumin-specific CD4 and CD8 T-cell responses were impaired in TLR4 antibody-injected OT-I and -II transgenic mice ex vivo. Adoptive transfer studies demonstrated suppression of OVA-specific CD4 and CD8 T-cell responses by the TLR4 antibody in vivo. The TLR4 antibody induced Gr1+ CD11b+ myeloid-derived suppressor cell (MDSC) expansion with suppression of T-cell activation. Monocytic MDSCs were more suppressive and exhibited higher expression of PD-L1 and inducible nitric oxidase compared with granulocytic MDSCs. In conclusion, immune tolerance conferred by TLR4 activation induces the expansion of monocytic MDSCs, which impairs antigen-specific T-cell priming and IgG production.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Activación de Linfocitos
/
Linfocitos
/
Epítopos de Linfocito T
/
Receptor Toll-Like 4
/
Células Supresoras de Origen Mieloide
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Eur J Immunol
Año:
2019
Tipo del documento:
Article
País de afiliación:
Japón