PPM1D-Mediated Regulation of the DNA Damage Repair Pathway in NK Cell Development and Migration

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.

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Journal
Journal of Human Immunity
Published
2025-04-25
DOI
https://doi.org/10.70962/cis2025abstract.110
Primary Topic
Immune Cell Function and Interaction
Type
article
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article

PPM1D-Mediated Regulation of the DNA Damage Repair Pathway in NK Cell Development and Migration

Kate Brown, Juan Francisco Quesada‐Espinosa, Agustin Gil Silva, Harry L. Malech et al.
Journal of Human Immunity
Immune Cell Function and Interaction
article

PPM1D-Mediated Regulation of the DNA Damage Repair Pathway in NK Cell Development and Migration

Kate Brown, Juan Francisco Quesada‐Espinosa, Agustin Gil Silva, Harry L. Malech, Hye Sun Kuehn, Emily Margaret Mace, José R. Regueiro, Laia Alsina, Leticia Pías, Ana V. Marín, Pierre Martine, Cathryn L. Haigh, Mercè Bolasell, Katherine R. Calvo, Colin L. Sweeney, Sergio D. Rosenzweig, David López-Pérez, Brigette Boast, Julie E. Niemela, Luis Ignacio González‐Granado, Ettore Apella, Seungmae Seo, Ana Esteve Sole, Kalpana Upadhyaya, Jennifer L. Stoddart
article en

Abstract

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.

Journal of Human ImmunityVol. 1(CIS2025)
National Institutes of Health (US), Hospital Sant Joan de Déu Barcelona (ES), Columbia University Irving Medical Center (US), Research Institute Hospital 12 de Octubre (ES), Hospital Universitario 12 De Octubre (ES), National Institute of Allergy and Infectious Diseases (US), National Cancer Institute (US), Center for Cancer Research (US), National Institutes of Health Clinical Center (US), Institut de Recerca Sant Joan de Déu, Columbia University (US)
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Immune Cell Function and Interaction
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