BMI-1 repression of the CD8 +T cell effector program is essential for memory formation

Abstract

Abstract NaïveCD8 +T cell activation results in a program of proliferation and differentiation that results in large scale changes in phenotype and function that is critical for pathogen control and establishment of immunological memory. While these changes are underpinned by structural and biochemical changes in genome regulatory elements, the mechanisms that mediate these changes are not fully elucidated. Polycomb Repressive complexes (PRC) are chromatin remodeling complexes implicated in silencing genes encoding crucial developmental regulators. We demonstrated that upregulation of PRC1 components occurs rapidly upon naïve CD8 +T cell activation and was associated with maintenance of ubiquitination at key effector transcriptional regulators. Importantly, in vitro activation of PRC1-deficient CD8 +T cells resulted in greater proliferation and more rapid acquisition of effector function compared to wildtype cells. Use of two different viral infection models demonstrated that T cell specific PRC1 deficiency resulted in a greater effector expansion and effector differentiation with establishment of dysfunctional memory T cell populations. Strikingly, even after acute infection, the resulting memory T cells exhibited phenotypic and molecular markers of T cell exhaustion and were unable to be recalled. Our data suggest that PRC1 regulation early after CD8 +T cell activation is essential for restraining early effector T cell commitment and is a key step in establishing immunological CD8 +T cell memory. Supported by grants from National Health and Medical Research Council of Australia (Ideas Grant 2020562).