Transcription factor p73 regulates Th1 differentiation

Nat Commun. 2020 Mar 19;11(1):1475. doi: 10.1038/s41467-020-15172-5.

Abstract

Inter-individual differences in T helper (Th) cell responses affect susceptibility to infectious, allergic and autoimmune diseases. To identify factors contributing to these response differences, here we analyze in vitro differentiated Th1 cells from 16 inbred mouse strains. Haplotype-based computational genetic analysis indicates that the p53 family protein, p73, affects Th1 differentiation. In cells differentiated under Th1 conditions in vitro, p73 negatively regulates IFNγ production. p73 binds within, or upstream of, and modulates the expression of Th1 differentiation-related genes such as Ifng and Il12rb2. Furthermore, in mouse experimental autoimmune encephalitis, p73-deficient mice have increased IFNγ production and less disease severity, whereas in an adoptive transfer model of inflammatory bowel disease, transfer of p73-deficient naïve CD4+ T cells increases Th1 responses and augments disease severity. Our results thus identify p73 as a negative regulator of the Th1 immune response, suggesting that p73 dysregulation may contribute to susceptibility to autoimmune disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Alleles
  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Differentiation*
  • Colitis / pathology
  • DNA / metabolism
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Deletion
  • Gene Expression Regulation
  • Interferon-gamma / metabolism
  • Mice
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Protein Binding
  • Protein Domains
  • Severity of Illness Index
  • Th1 Cells / cytology*
  • Th1 Cells / metabolism*
  • Tumor Protein p73 / chemistry
  • Tumor Protein p73 / deficiency
  • Tumor Protein p73 / genetics
  • Tumor Protein p73 / metabolism*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Mutant Proteins
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Interferon-gamma
  • DNA