Biallelic NFATC1 mutations cause an inborn error of immunity with impaired CD8+ T-cell function and perturbed glycolysis

Author:

Kostel Bal Sevgi12ORCID,Giuliani Sarah12ORCID,Block Jana123ORCID,Repiscak Peter1ORCID,Hafemeister Christoph1ORCID,Shahin Tala123ORCID,Kasap Nurhan45ORCID,Ransmayr Bernhard123,Miao Yirun123,van de Wetering Cheryl13ORCID,Frohne Alexandra12ORCID,Jimenez Heredia Raul12,Schuster Michael3ORCID,Zoghi Samaneh12ORCID,Hertlein Vanessa123ORCID,Thian Marini123ORCID,Bykov Aleksandr1ORCID,Babayeva Royala45ORCID,Bilgic Eltan Sevgi45ORCID,Karakoc-Aydiner Elif45,Shaw Lisa E.6ORCID,Chowdhury Iftekhar7ORCID,Varjosalo Markku7ORCID,Argüello Rafael J.8ORCID,Farlik Matthias6ORCID,Ozen Ahmet45ORCID,Serfling Edgar9,Dupré Loïc2610,Bock Christoph2311ORCID,Halbritter Florian1ORCID,Hannich J. Thomas3ORCID,Castanon Irinka12,Kraakman Michael J.12,Baris Safa45ORCID,Boztug Kaan1231213ORCID

Affiliation:

1. 1St. Anna Children’s Cancer Research Institute, Vienna, Austria

2. 2Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria

3. 3CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

4. 4Department of Pediatrics, Division of Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey

5. 5The Isil Berat Barlan Center for Translational Medicine, Marmara University, Istanbul, Turkey

6. 6Department of Dermatology, Medical University of Vienna, Vienna, Austria

7. 7Institute of Biotechnology, University of Helsinki, Helsinki, Finland

8. 8Aix Marseille University, CNRS, INSERM, CIML, Centre d’Immunologie de Marseille-Luminy, Marseille, France

9. 9Department of Molecular Pathology, Institute of Pathology, and Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany

10. 10Toulouse Institute for Infectious and Inflammatory Diseases, INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France

11. 11Medical University of Vienna, Institute of Artificial Intelligence, Center for Medical Data Science, Vienna, Austria

12. 12St. Anna Children’s Hospital, Vienna, Austria

13. 13Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria

Abstract

Abstract The nuclear factor of activated T cells (NFAT) family of transcription factors plays central roles in adaptive immunity in murine models; however, their contribution to human immune homeostasis remains poorly defined. In a multigenerational pedigree, we identified 3 patients who carry germ line biallelic missense variants in NFATC1, presenting with recurrent infections, hypogammaglobulinemia, and decreased antibody responses. The compound heterozygous NFATC1 variants identified in these patients caused decreased stability and reduced the binding of DNA and interacting proteins. We observed defects in early activation and proliferation of T and B cells from these patients, amenable to rescue upon genetic reconstitution. Stimulation induced early T-cell activation and proliferation responses were delayed but not lost, reaching that of healthy controls at day 7, indicative of an adaptive capacity of the cells. Assessment of the metabolic capacity of patient T cells revealed that NFATc1 dysfunction rendered T cells unable to engage in glycolysis after stimulation, although oxidative metabolic processes were intact. We hypothesized that NFATc1-mutant T cells could compensate for the energy deficit due to defective glycolysis by using enhanced lipid metabolism as an adaptation, leading to a delayed, but not lost, activation responses. Indeed, we observed increased 13C-labeled palmitate incorporation into citrate, indicating higher fatty acid oxidation, and we demonstrated that metformin and rosiglitazone improved patient T-cell effector functions. Collectively, enabled by our molecular dissection of the consequences of loss-of-function NFATC1 mutations and extending the role of NFATc1 in human immunity beyond receptor signaling, we provide evidence of metabolic plasticity in the context of impaired glycolysis observed in patient T cells, alleviating delayed effector responses.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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