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TP53INP1 deficiency maintains murine B lymphopoiesis in aged bone marrow through redox-controlled IL-7R/STAT5 signaling

Significance Reactive oxygen species (ROS) play a role in signaling in immune cells, in particular in B cell activation and terminal differentiation in secondary lymphoid organs. Nevertheless, their role in B cell development in the bone marrow (BM) still remains poorly explored. TP53INP1 is a target of the tumor suppressor p53, which mediates its antioxidant activity. We report the surprising observation that chronic oxidative stress in TP53INP1-deficient mice rescues B lymphopoiesis in the BM during aging. ROS sustain IL-7R signaling in aged TP53INP1-deficient BM through maintenance of active STAT5 transcription factor, driving the expression of the B lineage Pax5 transcription factor. This work suggests that antioxidants cannot be in favor of antibody-producing cell development. Bone marrow (BM) produces all blood and immune cells deriving from hematopoietic stem cells (HSCs). The decrease of immune cell production during aging is one of the features of immunosenescence. The impact of redox dysregulation in BM aging is still poorly understood. Here we use TP53INP1-deficient (KO) mice endowed with chronic oxidative stress to assess the influence of aging-associated redox alterations in BM homeostasis. We show that TP53INP1 deletion has no impact on aging-related accumulation of HSCs. In contrast, the aging-related contraction of the lymphoid compartment is mitigated in TP53INP1 KO mice. B cells that accumulate in old KO BM are differentiating cells that can mature into functional B cells. Importantly, this phenotype results from B cell-intrinsic events associated with defective redox control. Finally, we show that oxidative stress in aged TP53INP1-deficient mice maintains STAT5 expression and activation in early B cells, driving high Pax5 expression, which provides a molecular mechanism for maintenance of B cell development upon aging.