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Murine lupus susceptibility locus Sle1c2 mediates CD4+ T cell activation and maps to estrogen-related receptor γ

Perry, DJ;Yin, Y;Telarico, T;Baker, HV;Dozmorov, I;Perl, A;Morel, L;
Product: Pertussis Toxin from B. pertussis, Lyophilized in Buffer

Sle1c is a sublocus of the NZM2410-derived Sle1 major lupus susceptibility locus. We have shown previously that Sle1c contributes to lupus pathogenesis by conferring increased CD4(+) T cell activation and increased susceptibility to chronic graft-versus-host disease (cGVHD), which mapped to the centromeric portion of the locus. In this study, we have refined the centromeric sublocus to a 675-kb interval, termed Sle1c2. Mice from recombinant congenic strains expressing Sle1c2 exhibited increased CD4(+) T cell intrinsic activation and cGVHD susceptibility, similar to mice with the parental Sle1c. In addition, B6.Sle1c2 mice displayed a robust expansion of IFN-γ-expressing T cells. NZB complementation studies showed that Sle1c2 expression exacerbated B cell activation, autoantibody production, and renal pathology, verifying that Sle1c2 contributes to lupus pathogenesis. The Sle1c2 interval contains two genes, only one of which, Esrrg, is expressed in T cells. B6.Sle1c2 CD4(+) T cells expressed less Esrrg than B6 CD4(+) T cells, and Esrrg expression was correlated negatively with CD4(+) T cell activation. Esrrg encodes an orphan nuclear receptor that regulates oxidative metabolism and mitochondrial functions. In accordance with reduced Esrrg expression, B6.Sle1c2 CD4(+) T cells present reduced mitochondrial mass and altered mitochondrial functions as well as altered metabolic pathway utilization when compared with B6 CD4(+) T cells. Taken together, we propose Esrrg as a novel lupus susceptibility gene regulating CD4(+) T cell function through their mitochondrial metabolism.

PubMed ID: 22711888
226322632017-06-052017-06-0511:03:0111:03:012018-03-062018-03-0615:02:0015:02:00Perry, DJ;Yin, Y;Telarico, T;Baker, HV;Dozmorov, I;Perl, A;Morel, L;Perry, DJ;Yin, Y;Telarico, T;Baker, HV;Dozmorov, I;Perl, A;Morel, L;20122012Murine lupus susceptibility locus Sle1c2 mediates CD4+ T cell activation and maps to estrogen-related receptor γMurine lupus susceptibility locus Sle1c2 mediates CD4+ T cell activation and maps to estrogen-related receptor γJournal Of ImmunologyJournal Of Immunology793-803793-803189189222271188822711888

Sle1c is a sublocus of the NZM2410-derived Sle1 major lupus susceptibility locus. We have shown previously that Sle1c contributes to lupus pathogenesis by conferring increased CD4(+) T cell activation and increased susceptibility to chronic graft-versus-host disease (cGVHD), which mapped to the centromeric portion of the locus. In this study, we have refined the centromeric sublocus to a 675-kb interval, termed Sle1c2. Mice from recombinant congenic strains expressing Sle1c2 exhibited increased CD4(+) T cell intrinsic activation and cGVHD susceptibility, similar to mice with the parental Sle1c. In addition, B6.Sle1c2 mice displayed a robust expansion of IFN-γ-expressing T cells. NZB complementation studies showed that Sle1c2 expression exacerbated B cell activation, autoantibody production, and renal pathology, verifying that Sle1c2 contributes to lupus pathogenesis. The Sle1c2 interval contains two genes, only one of which, Esrrg, is expressed in T cells. B6.Sle1c2 CD4(+) T cells expressed less Esrrg than B6 CD4(+) T cells, and Esrrg expression was correlated negatively with CD4(+) T cell activation. Esrrg encodes an orphan nuclear receptor that regulates oxidative metabolism and mitochondrial functions. In accordance with reduced Esrrg expression, B6.Sle1c2 CD4(+) T cells present reduced mitochondrial mass and altered mitochondrial functions as well as altered metabolic pathway utilization when compared with B6 CD4(+) T cells. Taken together, we propose Esrrg as a novel lupus susceptibility gene regulating CD4(+) T cell function through their mitochondrial metabolism.

Sle1c is a sublocus of the NZM2410-derived Sle1 major lupus susceptibility locus. We have shown previously that Sle1c contributes to lupus pathogenesis by conferring increased CD4(+) T cell activation and increased susceptibility to chronic graft-versus-host disease (cGVHD), which mapped to the centromeric portion of the locus. In this study, we have refined the centromeric sublocus to a 675-kb interval, termed Sle1c2. Mice from recombinant congenic strains expressing Sle1c2 exhibited increased CD4(+) T cell intrinsic activation and cGVHD susceptibility, similar to mice with the parental Sle1c. In addition, B6.Sle1c2 mice displayed a robust expansion of IFN-γ-expressing T cells. NZB complementation studies showed that Sle1c2 expression exacerbated B cell activation, autoantibody production, and renal pathology, verifying that Sle1c2 contributes to lupus pathogenesis. The Sle1c2 interval contains two genes, only one of which, Esrrg, is expressed in T cells. B6.Sle1c2 CD4(+) T cells expressed less Esrrg than B6 CD4(+) T cells, and Esrrg expression was correlated negatively with CD4(+) T cell activation. Esrrg encodes an orphan nuclear receptor that regulates oxidative metabolism and mitochondrial functions. In accordance with reduced Esrrg expression, B6.Sle1c2 CD4(+) T cells present reduced mitochondrial mass and altered mitochondrial functions as well as altered metabolic pathway utilization when compared with B6 CD4(+) T cells. Taken together, we propose Esrrg as a novel lupus susceptibility gene regulating CD4(+) T cell function through their mitochondrial metabolism.

5.3625.362

Experimental autoimmune encephalomyelitis:

Experimental autoimmune encephalomyelitis was induced in 4-mo-old male B6 or B6.Sle1c2 mice. On day 0, mice received an emulsion of 50 mg myelin oligodendrocyte glycoprotein peptide sequence 35–55 and 500 mg Mycobacterium tuberculosis (Difco) in IFA (Sigma-Aldrich) via s.c. injections at the base of the tail. In addition, 500 ng pertussis toxin (List Biologicals) was administered i.p. on days 0 and 2. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

Experimental autoimmune encephalomyelitis:

Experimental autoimmune encephalomyelitis was induced in 4-mo-old male B6 or B6.Sle1c2 mice. On day 0, mice received an emulsion of 50 mg myelin oligodendrocyte glycoprotein peptide sequence 35–55 and 500 mg Mycobacterium tuberculosis (Difco) in IFA (Sigma-Aldrich) via s.c. injections at the base of the tail. In addition, 500 ng pertussis toxin (List Biologicals) was administered i.p. on days 0 and 2. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

http://www.jimmunol.org/content/189/2/793.shorthttp://www.jimmunol.org/content/189/2/793.short2012-07-152012-07-1510.4049/jimmunol.120041110.4049/jimmunol.1200411Pertussis Toxin from B. pertussis, Lyophilized in BufferPertussis Toxin from B. pertussis, Lyophilized in Buffermorel@ufl.edumorel@ufl.edu500;Activation;B cell;Cell;Clinical;Disease;Expressed;Expression;Function;Gene;Host;List;Metabolism;Murine;Novel;Paralysis;Pathogenesis;Pathology;Pathway;Pertussis;Production;Receptor;Recombinant;Studies;Study;T cell;Toxin;Journal Of Immunology500;Activation;B cell;Cell;Clinical;Disease;Expressed;Expression;Function;Gene;Host;List;Metabolism;Murine;Novel;Paralysis;Pathogenesis;Pathology;Pathway;Pertussis;Production;Receptor;Recombinant;Studies;Study;T cell;Toxin;Journal Of Immunology180180murine-lupus-susceptibility-locus-sle1c2murine-lupus-susceptibility-locus-sle1c2