Unified immune modulation by 4-1BB triggering leads to diverse effects on disease progression in vivo

4-1BB (CD137) is a powerful T-cell costimulatory molecule in the treatment of virus infections and tumors, but recent studies have also uncovered regulatory functions of 4-1BB signaling. Since 4-1BB triggering suppresses autoimmunity by accumulating indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) in an interferon (IFN)-γ-dependent manner, we asked whether similar molecular and cellular changes were induced by 4-1BB triggering in virus-infected mice. 4-1BB triggering increased IFN-γ and IDO, and suppressed CD4+ T cells, in C57BL/6 mice infected with the type 1 KOS strain of Herpes simplex virus (HSV-1), as it does in an autoimmune disease model. Detailed analysis of the CD4+ T suppression showed that freshly activated CD62Lhigh T cells underwent apoptosis in the early phase of suppression, and CD62Llow effector/memory T cells in the later phase. Although 4-1BB triggering resulted in similar cellular changes – increased CD8+ T and decreased CD4+ T cells, it had different effects on mortality in mice infected with HSV-1 RE, influenza, and Japanese encephalitis virus (JEV); it increased mortality in influenza-infected mice but decreased it in JEV-infected mice. Since the dominant type of immune cell generated to protect the host was different for each virus – CD4+ T cells and neutrophils in HSV-1 RE infection, both CD4+ T and CD8+ T cells in influenza infection, and a crucial role for B cells in JEV infection, 4-1BB triggering resulted in different therapeutic outcomes. We conclude that the therapeutic outcome of 4-1BB triggering is determined by whether the protective immunity generated against the virus was beneficially altered by the 4-1BB triggering.

► 4-1BB triggering suppresses autoimmunity through tryptophan catabolism induction. ► 4-1BB triggering similarly activates tryptophan metabolism in viral infection models. ► Similar cellular changes are induced by 4-1BB triggering in viral infection models. ► But 4-1BB triggering causes different therapeutic outcomes in the infection models.