Effect of p53 activation through targeting MDM2/MDM4 heterodimer on T regulatory and effector cells in the peripheral blood of Type 1 diabetes patients

Marsha Pellegrino; Gianandrea Traversi; Andrea Arena; Marco Cappa; M Manuela Rosado; Marco Andreani; Domenico V Delfino; Fabiola Moretti; Alessandra Fierabracci

doi:10.1371/journal.pone.0228296

Effect of p53 activation through targeting MDM2/MDM4 heterodimer on T regulatory and effector cells in the peripheral blood of Type 1 diabetes patients

PLoS One. 2020 Jan 29;15(1):e0228296. doi: 10.1371/journal.pone.0228296. eCollection 2020.

Authors

Marsha Pellegrino¹, Gianandrea Traversi¹, Andrea Arena¹, Marco Cappa², M Manuela Rosado³, Marco Andreani⁴, Domenico V Delfino⁵, Fabiola Moretti⁶, Alessandra Fierabracci¹

Affiliations

¹ Infectivology and Clinical Trials Research Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
² Endocrinology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
³ Research Laboratories, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁴ Transplantation Immunogenetics Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
⁵ Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy.
⁶ Institute of Cell Biology and Neurobiology, National Research Council of Italy (CNR), Rome, Italy.

Abstract

Various immunotherapies for the treatment of type 1 diabetes are currently under investigation. Some of these aim to rescue the remaining beta cells from autoimmune attack caused by the disease. Among the strategies employed, p53 has been envisaged as a possible target for immunomodulation. We studied the possible effect of p53 activation on Treg subsets and Treg/Teff balance in type 1 diabetes patients' PBMC. Upon p53 activation, we observed an increase in CD8+ Treg and activated CD8+ Teff whilst CD8+ Teff cells significantly decreased in healthy PBMC when stimulated with anti-CD3/CD28. No effect was detected on percentages of CD4+ Treg, while a reduction was seen in CD4+ Teff cells and an increase in activated CD4+ Teff cells. In patients' PBMC, upon p53 activation followed by 6 days of anti-CD3/CD28 stimulation, CD8+ Treg and activated CD8+ Teff were increased while CD8+ Teff were decreased. No differences were detected in the CD4+ counterparts. CD8+ Teff PD1+, CD8+ Teff PD1low were increased upon p53 activation in type 1 diabetics compared to controls while CD8+ Teff PD1high were increased in both groups. The same increased percentages were detected for CD4+ counterparts. CD4+ Treg PD1high cells were decreased in diabetics upon p53 activation at day 6 of anti-CD3/CD28 stimulation. In conclusion, a Teff dysregulation is observed upon p53 activation suggesting that molecules promoting p53 cannot be used for therapy in type 1 diabetics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
CD8-Positive T-Lymphocytes / metabolism
Case-Control Studies
Cell Cycle Proteins / metabolism
Diabetes Mellitus, Type 1 / genetics
Diabetes Mellitus, Type 1 / immunology*
Female
Humans
Imidazoles / pharmacology*
Leukocytes, Mononuclear / drug effects*
Leukocytes, Mononuclear / immunology
Male
Multiprotein Complexes / antagonists & inhibitors*
Peptides / pharmacology*
Piperazines / pharmacology*
Polymorphism, Genetic
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-mdm2 / metabolism
T-Lymphocytes, Regulatory / metabolism*
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / genetics
Young Adult

Substances

Cell Cycle Proteins
Imidazoles
MDM4 protein, human
Multiprotein Complexes
Peptides
Piperazines
Proto-Oncogene Proteins
TP53 protein, human
Tumor Suppressor Protein p53
nutlin 3
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2

Grants and funding

AF 201802P004265 Italian Ministry of Health Ricerca Corrente FM IG 21814 AIRC (Associazione Italiana Ricerca sul Cancro) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.