The transcription factor NFAT1 participates in the induction of CD4+ T cell functional exhaustion during Plasmodium yoelii infection

Rachel Y. Ames, Li Min Ting, Inessa Gendlina, Kami Kim, Fernando Macian

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Repeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and upregulate cell surface inhibitory molecules such as PD-1 and LAG-3. The molecular events that lead to the induction of this phenotype have, however, not been fully characterized. In T cells, members of the NFAT family of transcription factors not only are responsible for the expression of many activation-induced genes but also are crucial for the induction of transcriptional programs that inhibit T cell activation and maintain tolerance. Here we show that NFAT1-deficient CD4+ T cells maintain higher proliferative capacity and expression of effector cytokines following Plasmodium yoelii infection and are therefore more resistant to P. yoelii-induced exhaustion than their wild-type counterparts. Consequently, gene expression microarray analysis of CD4+ T cells following P. yoeliiinduced exhaustion shows upregulation of effector T cell-associated genes in the absence of NFAT1 compared with wild-type exhausted T cells. Furthermore, adoptive transfer of NFAT1-deficient CD4+ T cells into mice infected with P. yoelii results in increased production of antibodies to cognate antigen. Our results support the idea that NFAT1 is necessary to fully suppress effector responses during Plasmodiuminduced CD4+ T cell exhaustion.

Original languageEnglish (US)
Article numbere00364-17
JournalInfection and Immunity
Volume85
Issue number9
DOIs
StatePublished - Sep 1 2017

Fingerprint

Plasmodium yoelii
Malaria
Transcription Factors
T-Lymphocytes
Up-Regulation
Infection
Cytokines
Phenotype
Antigens
Adoptive Transfer
Microarray Analysis
Surface Antigens
Transcriptional Activation
Antibody Formation

Keywords

  • Exhaustion
  • NFAT
  • Plasmodium
  • T cells

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

Cite this

The transcription factor NFAT1 participates in the induction of CD4+ T cell functional exhaustion during Plasmodium yoelii infection. / Ames, Rachel Y.; Ting, Li Min; Gendlina, Inessa; Kim, Kami; Macian, Fernando.

In: Infection and Immunity, Vol. 85, No. 9, e00364-17, 01.09.2017.

Research output: Contribution to journalArticle

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