PPM1D is a phosphatase that regulates the DNA damage response (DDR) by dephosphorylating some of its key players, including p53 and gH2AX. Inborn errors of immunity (IEI) with altered DDR have been associated with natural killer (NK) cell deficiency, including helicase deficiencies with increased p53 and gH2AX phosphorylation after activation.
We evaluated two patients with a syndromic IEI caused by biallelic loss of function of PPM1D with B and NK cell deficiency. Besides the reduction in peripheral blood NK cell number and frequency, the patients also showed increased immature NK cells (CD56+CD62L+) and decreased mature NK cells (CD56+CD57+), while degranulation function was preserved. To investigate the role of PPM1D in NK cell maturation, we evaluated NK cell development from induced pluripotent cells in the presence of a PPM1D inhibitor (PPM1Di). PPM1Di led to a significant decrease in viability during the first stages of development and premature NK cell differentiation, followed by a reduction in NK cell frequency at endpoint, particularly impacting terminally mature NK cells. NK cell evaluation in Ppm1d-KO mice revealed an accumulation of mature NK cells in the bone marrow relative to progenitor cells. This abnormal NK cell distribution also included conserved NK cell numbers in the spleen with decreased expression of maturation markers and a relative reduction of NK cells in the blood. Analysis of healthy control human tonsil and blood NK cell subset bulk transcriptomics (GSE169646) showed higher expression of PPM1D in peripheral blood NK cell subsets compared with equivalent tonsil maturation stages, altogether indicating the relevance of PPM1D for NK cell tissue distribution and homeostasis.
