Hematopoietic cell-specific knockout Hspa9 impairs natural killer cell function and alters the Akt/mTOR axis in mice

Natural killer (NK) cells are crucial components of the innate immune system, serving vital roles in tumor killing and antiviral immunity. Heat shock protein family A (Hsp70) member 9 (Hspa9), a molecular chaperone localized to the mitochondrial matrix and inner membrane, is essential for maintaining mitochondrial homeostasis. However, its role in regulating NK cells remains unclear. The present study aimed to investigate the impact of the Hspa9 on NK cell regulation and its underlying molecular mechanism. By knocking out Hspa9 at the hematopoietic cell stage, NK cell numbers were found to be markedly reduced in the spleen, bone marrow and liver of mice. Hspa9-deficient NK cells exhibited significantly reduced IFN-γ secretion and CD107a expression. Mechanistically, Hspa9 deficiency led to perturbed expression of surface receptors CD117, CD127 and killer cell lectin-like receptor subfamily A, member 9, which may underlie the observed alteration in maturation status. Furthermore, the impaired NK cell function may be associated with suppressed activation of the Akt/mTOR signaling pathway. In summary, the present study reveals a novel role for Hspa9 in regulating NK cell function, proposes a potential regulatory mechanism and identifies Hspa9 as a promising molecular target for modulating NK cell biology.