Regulation of immune homeostasis, autoimmunity and protective immunity by the CD160 and PD-1 co-inhibitory molecules

Abstract

Co-stimulatory and co-inhibitory pathways are critical for immune homeostasis, immune tolerance and protective immunity. In this thesis, we analyzed how two co-inhibitory molecules, CD160 and programmed cell death-1 (PD-1), regulate immune homeostasis, autoimmunity and protective immunity. The function of CD160 on T cells remains unclear with conflicting studies supporting both co-inhibitory and co-stimulatory roles. Here we demonstrate that CD160 has a co-stimulatory role in promoting CD8+ T cell effector functions needed for optimal clearance of oral Listeria monocytogenes (Lm) infection. CD160–/– mice did not clear oral Lm as efficiently as WT littermates. Defective bacterial clearance is due to compromised IEL and splenic CD8+ T cell functions – reduced granzyme B, TNF-α and IFN-γ production in CD160–/– IELs and splenic CD8+ T cells. Adoptive transfer studies showed that RAG–/– recipients receiving CD160–/– CD8+ T cells had a higher mortality and a higher bacteria burden compared to RAG–/– recipients receiving WT CD8+ T cells. These findings demonstrate that CD160 provides key co-stimulatory signals to CD8+ T cells for protective immunity during an acute mucosal bacteria infection. Secondly, we studied the role of PD-1 on regulatory T cells (Tregs). The PD-1 co-inhibitory pathway is critical for immune tolerance. Studies of PD-1 function have focused primarily on effector T cells, and little is known about how PD-1 regulates Tregs, which are critical for maintaining the balance between tolerance and immunity. We demonstrated that PD-1 deficient Tregs have increased suppressive capacity in vitro and in vivo compared to WT Tregs. Mice lacking PD-1 selectively on Tregs had delayed onset and severity of experimental autoimmune encephalitis (EAE) and were protected against diabetes in non-obese diabetic (NOD) mice. The enhanced suppressive capacity in PD-1 deficient Tregs is due to down-regulation of the PI3K-AKT pathway in Tregs and PD-1 deficient Tregs have altered bioenergetics. Our findings demonstrate that signals through PD-1 in Treg cells restrain their activation and function and are vital for optimal homeostasis, protective immunity and tolerance. These findings advance our mechanistic understanding of how co-inhibitory molecules on different immune cell types regulate immune homeostasis, autoimmunity and immunity.