NLRX1 Regulates Effector and Metabolic Functions of CD4+ T Cells.

Abstract

Nucleotide oligomerization domain-like receptor X1 (NLRX1) has been implicated in viral response, cancer progression, and inflammatory disorders; however, its role as a dual modulator of CD4+ T cell function and metabolism has not been defined. The loss of NLRX1 results in increased disease severity, populations of Th1 and Th17 cells, and inflammatory markers (IFN-γ, TNF-α, and IL-17) in mice with dextran sodium sulfate-induced colitis. To further characterize this phenotype, we used in vitro CD4+ T cell-differentiation assays and show that NLRX1-deficient T cells have a greater ability to differentiate into an inflammatory phenotype and possess greater proliferation rates. Further, NLRX1-/- cells have a decreased responsiveness to immune checkpoint pathways and greater rates of lactate dehydrogenase activity. When metabolic effects of the knockout are impaired, NLRX1-deficient cells do not display significant differences in differentiation or proliferation. To confirm the role of NLRX1 specifically in T cells, we used an adoptive-transfer model of colitis. Rag2-/- mice receiving NLRX1-/- naive or effector T cells experienced increased disease activity and effector T cell populations, whereas no differences were observed between groups receiving wild-type or NLRX1-/- regulatory T cells. Metabolic effects of NLRX1 deficiency are observed in a CD4-specific knockout of NLRX1 within a Citrobacter rodentium model of colitis. The aerobic glycolytic preference in NLRX1-/- effector T cells is combined with a decreased sensitivity to immunosuppressive checkpoint pathways to provide greater proliferative capabilities and an inflammatory phenotype bias leading to increased disease severity.

• Authors: Andrew Leber, Raquel Hontecillas, Nuria Tubau-Juni, Victoria Zoccoli-Rodriguez, Matthew Hulver, Ryan McMillan, Kristin Eden, Irving C Allen, Josep Bassaganya-Riera
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 198 Issue 6 Pg. 2260-2268 (03 15 2017) ISSN: 1550-6606 [Electronic] United States
• PMID: 28159898 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 by The American Association of Immunologists, Inc.

Chemical References

• Interleukin-17
• Mitochondrial Proteins
• NLRX1 protein, mouse
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• Dextran Sulfate

Topics

• Adoptive Transfer
• Animals
• Cell Proliferation (genetics)
• Cells, Cultured
• Citrobacter rodentium (immunology)
• Colitis (chemically induced, immunology)
• Dextran Sulfate
• Disease Models, Animal
• Enterobacteriaceae Infections (immunology)
• Humans
• Inflammatory Bowel Diseases (immunology)
• Interferon-gamma (metabolism)
• Interleukin-17 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondrial Proteins (genetics, metabolism)
• T-Lymphocytes, Regulatory (immunology)
• Th1 Cells (immunology)
• Th2 Cells (immunology)
• Tumor Necrosis Factor-alpha (metabolism)