Transcriptional control of impaired Th1 responses in patent lymphatic filariasis by T-box expressed in T cells and suppressor of cytokine signaling genes

Infect Immun. 2005 Jun;73(6):3394-401. doi: 10.1128/IAI.73.6.3394-3401.2005.

Abstract

T-bet (T-box expressed in T cells) and GATA-3 are transcription factors that play a critical role in the development of Th1 and Th2 cells, as do genes of the SOCS (suppressor of cytokine signaling) family, albeit indirectly. Another transcription factor, Foxp3, is a master regulator of natural regulatory T cells (Tregs). To identify the role of these factors in impaired Th1 responses of patent filarial infection, analysis of cytokine, SOCS, and transcription factor mRNA expression was performed on purified T cells of filaria-infected individuals (n = 6) and uninfected controls (n = 6). As expected (and in contrast to cells of uninfected individuals), there was a significant depression of gamma interferon (IFN-gamma) and a concomitant increase in interleukin-4 (IL-4), IL-5, and IL-10 mRNA expression following stimulation with parasite antigen (BmA) but not with a polyclonal T-cell (anti-CD3) stimulus. T-bet (but not GATA-3) was expressed at significantly lower levels in cells of filaria-infected individuals in response to BmA compared with those from the uninfected group, accounting, at least partially, for the diminished IFN-gamma expression. Second, we found no significant differences in expression of Foxp3 between the two groups, although induction of Foxp3 expression correlated with induced expression levels of IL-10, implicating Tregs in the IL-10 expression seen. Finally, parasite-specific T-cell expression of SOCS-1, SOCS-5, and SOCS-7 was significantly diminished among infected patients; in contrast, expression of SOCS-3 increased. Our data therefore indicate that the impaired Th1 responses observed in patent lymphatic filariasis are associated with decreased expression of T-bet, SOCS-1, SOCS-5, and SOCS-7 and increased expression of SOCS-3 in T cells.

MeSH terms

  • Adult
  • Antigens, Helminth / immunology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Elephantiasis, Filarial / immunology*
  • Female
  • Forkhead Transcription Factors
  • GATA3 Transcription Factor
  • Humans
  • Interferon-gamma / biosynthesis*
  • Interleukin-10 / biosynthesis
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics*
  • Proteins / genetics*
  • Repressor Proteins / genetics*
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • T-Box Domain Proteins
  • Th1 Cells / immunology*
  • Trans-Activators / genetics
  • Trans-Activators / physiology
  • Transcription Factors / genetics*
  • Transcription Factors / physiology*
  • Transcription, Genetic*

Substances

  • Antigens, Helminth
  • DNA-Binding Proteins
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • GATA3 Transcription Factor
  • GATA3 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Proteins
  • Repressor Proteins
  • SOCS1 protein, human
  • SOCS3 protein, human
  • SOCS5 protein, human
  • SOCS7 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • T-Box Domain Proteins
  • T-box transcription factor TBX21
  • Trans-Activators
  • Transcription Factors
  • Interleukin-10
  • Interferon-gamma