Abstract
The protozoan parasite, Toxoplasma, like many intracellular pathogens, suppresses interferon gamma (IFN-γ)-induced signal transducer and activator of transcription 1 (STAT1) activity. We exploited this well-defined host–pathogen interaction as the basis for a high-throughput screen, identifying nine transcription factors that enhance STAT1 function in the nucleus, including the orphan nuclear hormone receptor TLX. Expression profiling revealed that upon IFN-γ treatment TLX enhances the output of a subset of IFN-γ target genes, which we found is dependent on TLX binding at those loci. Moreover, infection of TLX deficient mice with the intracellular parasite Toxoplasma results in impaired production of the STAT1-dependent cytokine interleukin-12 by dendritic cells and increased parasite burden in the brain during chronic infection. These results demonstrate a previously unrecognized role for this orphan nuclear hormone receptor in regulating STAT1 signaling and host defense and reveal that STAT1 activity can be modulated in a context-specific manner by such “modifiers.”
Highlights
Interferon gamma (IFN-γ) and signal transducer and activator of transcription 1 (STAT1) signaling play an essential role in cellular immunity, as indicated by extreme susceptibility to infection in mice and humans carrying mutant alleles for these genes and pathways [1,2,3,4,5]
These data are consistent with previous reports [29,30,31,32,33], which indicate that Toxoplasma impairs STAT1 signaling by acting downstream in the pathway, at the level of nuclear STAT1 function (S1F Fig)
The orphan nuclear receptor TLX was amongst the strongest STAT1 enhancers identified, and we have shown that TLX enhances the expression of endogenous STAT1 target genes following interferon gamma (IFN-γ) stimulation but is required for control of Toxoplasma infection
Summary
Interferon gamma (IFN-γ) and STAT1 signaling play an essential role in cellular immunity, as indicated by extreme susceptibility to infection in mice and humans carrying mutant alleles for these genes and pathways [1,2,3,4,5]. While STAT1 signaling suppresses cell proliferation during hematopoiesis [11,12], IFN-γ-induced STAT1 signaling can drive hematopoietic stem cells to enter the cell cycle and proliferate to replace leukocytes lost during infection [13]. This apparent duality of STAT1 function extends to additional immune cells: STAT1 signaling in macrophages activates a potent antimicrobial program and promotes antigen processing and presentation to T cells, yet STAT1 is required for the ability of tumor-associated macrophages to suppress T cell function [14]. The diversity of outcomes associated with STAT1 activation highlights the need to identify the cellular factors that modify or modulate STAT1 target selection to appropriately tailor the output of this core signaling pathway
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