Type I interferon regulates GITRL on infiltrating monocyte-derived inflammatory APC to establish early viral control during chronic LCMV infection
| Autor: | Yu-Han Chang, Angela Zhou, Ali Abdul-Sater, Tania H Watts |
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| Rok vydání: | 2016 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 196:196.11-196.11 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | Disease outcome in chronic viral infections correlates with early viral set-point established by the initial T cell response. Previous studies showed that GITR, an NFκB-activating TNFR family member, sustains CD4 T cell accumulation and help for CD8 T cells at the onset of chronic LCMV infection. While the endogenous effect of GITR on CD8 T cells is largely attributed to enhanced early CD4 T cell help, CD8 T cells are directly responsive to exogenous GITR agonist. How endogenous GITR co-stimulation selectively impacts CD4 T cells early post-LCMV infection (p.i.), however, remains elusive. We hypothesize that CD4 and CD8 T cells interact with distinct antigen presenting cells (APC) and that the availability of GITRL underscores the regulation of GITR co-stimulation. Herein, we identify inflammatory monocyte-derived DC and macrophages (infMΦ) as the dominant GITRL-expressing APC with approximately 5 times higher levels compared to classical DC during LCMV infection. A preliminary experiment showed that deleting exon 2 of GITRL using MΦ-specific Lys-M-Cre recapitulates the marked reduction in Th1 response against LCMV observed in the whole-body GITR knockout. GITRL exhibits similar expression kinetics to type I interferon (IFN-I) with an early but transient peak at 24–48 hours p.i. IFN-I is a potent inducer of GITRL on thioglycollate-elicited peritoneal macrophages (TG-MΦ) ex vivo. Moreover, blockade of IFN-I receptor abrogates up-regulation of GITRL during LCMV infection of TG-MΦ in vitro, as well as on infMΦ in vivo. Together, the current study suggests a critical role for infMΦ in GITR-dependent immunity to LCMV and identifies IFN-I as a key regulator of GITRL on infMΦ in vivo. |
| Databáze: | OpenAIRE |
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