Loss of the nuclear receptor PPARγ primes CD8+ T cells for exhaustion

Abstract

Abstract Peroxisome proliferator activated receptors (PPARs) are transcription factors that belong to nuclear hormone superfamily, with three distinct types identified: PPARapha (PPARα), PPARgamma (PPARγ), and PPARbeta/delta (PPARβ/δ). The role of PPARγ in the immune system has been mainly studied in macrophages, where it is known to mediate M2 polarization. Synthetic ligands for activating PPARγ ameliorate disease outcomes in various models of inflammation and autoimmunity. Here, we investigated how PPARγ affects antigen-specific effector and memory responses of CD8+ T cells using OT-I TCR transgenic mice and OT-I mice with T cell-specific PPARγ deletion. During CD8+ T effector differentiation in vitro by IL-2 culture following stimulation with cognate antigen, PPARγ deletion resulted in a rapid and enhanced T effector cell expansion and activation. However, PPARγ deficient OTI cells were more prone to exhaustion. This effect coincided with decreased mitochondrial fitness and spare respiratory capacity, high ROS levels and a significant increase in oxidized lipids. During generation of T effector cells in vivo, PPARγ deletion resulted in similar outcomes. At the memory phase there were no numerical differences in the T memory subsets in vivo, but upon rechallenge in vitro, PPARγ-deficient antigen-specific T cells had impaired capacity for effector differentiation. Our findings uncover a new role of PPARγ in CD8+ T responses and indicate that PPARγ has an indispensable role in regulating metabolism-mediated cues that imprint T cell differentiation and long-term effector capacity. Supported by RO1CA212605, RO1CA229784-01, RO1CA238263 (to VAB)