4-1BB Triggering Ameliorates Experimental Autoimmune Encephalomyelitis by Modulating the Balance between Th17 and Regulatory T Cells

Abstract

Agonistic anti–4-1BB Ab is known to ameliorate experimental autoimmune encephalomyelitis. 4-1BB triggering typically leads to the expansion of CD8+ T cells, which produce abundant IFN-γ, and this in turn results in IDO-dependent suppression of autoimmune responses. However, because neutralization of IFN-γ or depletion of CD8+ T cell only partially abrogates the effect of 4-1BB triggering, we sought to identify an additional mechanism of 4-1BB–triggered suppression of autoimmune responses using IFN-γ- or IFN-γR–deficient mice. 4-1BB triggering inhibited the generation of Th17 cells that is responsible for experimental autoimmune encephalomyelitis induction and progression, and increased Foxp3+CD4+ regulatory T (Treg) cells, particularly among CD4+ T cells. This was not due to a direct effect of 4-1BB signaling on CD4+ T cell differentiation: 4-1BB signaling not only reduced Th17 cells and increased Treg cells in wild-type mice, which could be due to IFN-γ production by the CD8+ T cells, but also did so in IFN-γ–deficient mice, in that case by downregulating IL-6 production. These results show that although secondary suppressive mechanisms evoked by 4-1BB triggering are usually masked by the strong effects of IFN-γ, 4-1BB signaling seems to modulate autoimmune responses by a number of mechanisms, and modulation of the Th17 versus Treg cell balance is one of those mechanisms.

Development of Experimental Autoimmune Encephalomyelitis Critically Depends on CD137 Ligand Signaling

“…In contrast to our findings, two studies observed that stimulation of CD137 using an agonistic anti-CD137 antibody reduced the severity of EAE (Sun et al, 2002;Kim et al, 2011). Stimulating CD137 in vivo using an agonistic antibody overactivated T cells, which lead to deletion of pathogenic T cells.…”

“…These results suggest that T regs do not contribute to the protection of CD137L Ϫ/Ϫ mice from EAE. Another explanation for the differences observed by Sun et al (2002) and Kim et al (2011) and our study may be due to the bidirectional signaling in CD137-CD137L system. The use of agonistic anti-CD137 antibody is expected to maintain or even enhance signaling through CD137 while signaling through CD137L would be reduced as CD137 is bound to the antibody.…”

“…Decreased EAE susceptibility of CD137L ؊/؊ mice Previous studies indicated a role for CD137 and its ligand in MS (Sharief, 2002;Liu et al, 2006Liu et al, , 2008. To gain further insight into the role of CD137-CD137L in EAE, we immunized wild-type (WT) and CD137L Ϫ/Ϫ mice with MOG 35-55 peptide.…”

“…Several costimulatory molecules belonging to the TNFR/TNF superfamily have been implicated in EAE (Racke et al, 2000). For instance, CD137 (4-1BB, TNFRSF9) and CD137 ligand (CD137L, 4-1BB ligand, TNFS9) are increased in serum and CSF of MS patients (Sharief, 2002;Liu et al, 2006Liu et al, , 2008. CD137 is mainly expressed by activated T-cells but can also be expressed by dendritic cells, natural killer (NK) cells, neutrophils, and endothelial cells.…”

Pertussis Toxin Exacerbates and Prolongs Airway Inflammatory Responses during Bordetella pertussis Infection

“…Lipocalin-2, a molecule involved in antimicrobial defense (28), protects against airway inflammation in a mouse model of allergic asthma (23). In addition, the tumor necrosis factor receptor superfamily 9 protein (Tnfrsf9) was shown previously to push the balance between Th17 cells and Tregs in favor of Treg generation (40). Finally, zinc finger protein 36 was reported previously to bind and destabilize cytokine mRNAs to reduce inflammatory responses (13).…”