NLRX1 Regulates Effector and Metabolic Functions of CD4+T Cells.
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 aCitrobacter rodentiummodel 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.
Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA 24061.
Andrew
0000-0001-9765-4702
A
Leber
Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA 24061.
Raquel
0000-0003-2942-6294
R
Hontecillas
Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA 24061.
Nuria
0000-0002-5787-8055
N
Tubau-Juni
Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA 24061.
Victoria
0000-0002-5487-6521
V
Zoccoli-Rodriguez
Metabolic Phenotyping Core, Virginia Tech, Blacksburg, VA 24061.|Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA 24061; and.
Matthew
M
Hulver
Metabolic Phenotyping Core, Virginia Tech, Blacksburg, VA 24061.|Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blacksburg, VA 24061; and.
Ryan
R
McMillan
Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA 24061.|Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Kristin
0000-0001-5309-5830
K
Eden
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
Irving C
0000-0001-9573-5250
IC
Allen
Nutritional Immunology and Molecular Medicine Laboratory, Biocomplexity Institute of Virginia Tech, Blacksburg, VA 24061; jbassaga@vt.edu.
Josep
J
Bassaganya-Riera
D019264:Adoptive Transfer; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D044082:Citrobacter rodentium / Q000276:immunology*; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004756:Enterobacteriaceae Infections / Q000276:immunology*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D020381:Interleukin-17; D024101:Mitochondrial Proteins; C555655:NLRX1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D016264:Dextran Sulfate