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The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function.

Barnes MJ, Li CM, Xu Y, An J, Huang Y, Cyster JG - J. Exp. Med. (2015)

Bottom Line: In vivo, LysoPS was detected in lymphoid organ and spinal cord tissues and was abundant in the colon.This study provides evidence that a bioactive lipid, LysoPS, negatively influences T reg cell accumulation and activity through GPR174.As such, GPR174 antagonists might have therapeutic potential for promoting immune regulation in the context of autoimmune disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, and Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute, Department of Microbiology and Immunology, and Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143.

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GPR174 deficiency in T reg cells limits the severity of EAE. (A) EAE was induced in 10-wk-old male wild-type or Gpr174−/Y littermate mice by injecting a MOG35–55 + CFA emulsion (s.c.) followed by pertussis toxin (i.v.). Mice were scored daily for disease symptoms; mean disease scores are shown and error bars indicate SEM. (B) The frequency of Foxp3+ T reg cells among total CD4+ T cells was determined in the indicated tissues 12 d after EAE induction in 10-wk-old male wild-type or Gpr174−/Y littermate mice by flow cytometry. (C) EAE was induced in a cohort of wild-type mice, and levels of LysoPS were measured by LC-MS/MS in the inguinal LN that drained the MOG + CFA emulsion (dotted lines) and in the spinal cord (solid lines) throughout the course of disease; n = 3–5. (B and C) Error bars show SD. (D) EAE was induced in 10-wk-old female Gpr174+/− or wild-type littermate mice as in A; error bars show SEM. (E and F) In Gpr174+/− or wild-type female mice heterozygous for an X-linked Foxp3-DTR allele, diphtheria toxin (DTx) was injected on days −10, −7, and −4. EAE was induced as in A on day 0. The ablation efficiency was assessed by analyzing the frequency of DTR-GFP+ cells among blood CD4+CD25+ T reg cells at the indicated time points (E); error bars show SD. Disease was scored daily after MOG immunization (F); n = 11; error bars show SEM. Data are representative of two (E and F) or three or more (A–D) independent experiments. Differences between groups were compared using unpaired Student’s t test for each time point: *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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fig5: GPR174 deficiency in T reg cells limits the severity of EAE. (A) EAE was induced in 10-wk-old male wild-type or Gpr174−/Y littermate mice by injecting a MOG35–55 + CFA emulsion (s.c.) followed by pertussis toxin (i.v.). Mice were scored daily for disease symptoms; mean disease scores are shown and error bars indicate SEM. (B) The frequency of Foxp3+ T reg cells among total CD4+ T cells was determined in the indicated tissues 12 d after EAE induction in 10-wk-old male wild-type or Gpr174−/Y littermate mice by flow cytometry. (C) EAE was induced in a cohort of wild-type mice, and levels of LysoPS were measured by LC-MS/MS in the inguinal LN that drained the MOG + CFA emulsion (dotted lines) and in the spinal cord (solid lines) throughout the course of disease; n = 3–5. (B and C) Error bars show SD. (D) EAE was induced in 10-wk-old female Gpr174+/− or wild-type littermate mice as in A; error bars show SEM. (E and F) In Gpr174+/− or wild-type female mice heterozygous for an X-linked Foxp3-DTR allele, diphtheria toxin (DTx) was injected on days −10, −7, and −4. EAE was induced as in A on day 0. The ablation efficiency was assessed by analyzing the frequency of DTR-GFP+ cells among blood CD4+CD25+ T reg cells at the indicated time points (E); error bars show SD. Disease was scored daily after MOG immunization (F); n = 11; error bars show SEM. Data are representative of two (E and F) or three or more (A–D) independent experiments. Differences between groups were compared using unpaired Student’s t test for each time point: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Mentions: Finally, given the constraining influence of GPR174 on T reg cell development and functionality, we examined whether GPR174 deficiency might protect mice from autoimmune pathology. To induce EAE, we administered myelin oligodendrocyte glycoprotein (MOG) peptide in CFA along with pertussis toxin. In this disease model, Th1 and Th17 cells drive CNS inflammation, whereas T reg cells can limit disease severity and promote the remission of symptoms (Stromnes and Goverman, 2006). Although the day of disease onset was unaffected, Gpr174−/Y male mice showed significantly reduced peak disease severity compared with wild-type littermates (Fig. 5 A). At day 12, a time point when Gpr174−/Y and wild-type mice showed a similar disease score, the frequency of Foxp3+ T reg cells was not significantly affected by GPR174 deficiency in the secondary lymphoid organs or spinal cord (Fig. 5 B); however, the frequency of CD103+ cells among T reg cells remained elevated in the draining LN at days 8–12 (not depicted). Moreover, levels of 16:0, 18:0, and 18:1 LysoPS did not appear to markedly change in the draining LN or spinal cord throughout the experiment (Fig. 5 C). These whole tissue analyses do not exclude the possibility that there are changes in other LysoPS isoforms (Blankman et al., 2013; Kamat et al., 2015) or local changes in interstitial LysoPS concentrations that affect cell behavior.


The lysophosphatidylserine receptor GPR174 constrains regulatory T cell development and function.

Barnes MJ, Li CM, Xu Y, An J, Huang Y, Cyster JG - J. Exp. Med. (2015)

GPR174 deficiency in T reg cells limits the severity of EAE. (A) EAE was induced in 10-wk-old male wild-type or Gpr174−/Y littermate mice by injecting a MOG35–55 + CFA emulsion (s.c.) followed by pertussis toxin (i.v.). Mice were scored daily for disease symptoms; mean disease scores are shown and error bars indicate SEM. (B) The frequency of Foxp3+ T reg cells among total CD4+ T cells was determined in the indicated tissues 12 d after EAE induction in 10-wk-old male wild-type or Gpr174−/Y littermate mice by flow cytometry. (C) EAE was induced in a cohort of wild-type mice, and levels of LysoPS were measured by LC-MS/MS in the inguinal LN that drained the MOG + CFA emulsion (dotted lines) and in the spinal cord (solid lines) throughout the course of disease; n = 3–5. (B and C) Error bars show SD. (D) EAE was induced in 10-wk-old female Gpr174+/− or wild-type littermate mice as in A; error bars show SEM. (E and F) In Gpr174+/− or wild-type female mice heterozygous for an X-linked Foxp3-DTR allele, diphtheria toxin (DTx) was injected on days −10, −7, and −4. EAE was induced as in A on day 0. The ablation efficiency was assessed by analyzing the frequency of DTR-GFP+ cells among blood CD4+CD25+ T reg cells at the indicated time points (E); error bars show SD. Disease was scored daily after MOG immunization (F); n = 11; error bars show SEM. Data are representative of two (E and F) or three or more (A–D) independent experiments. Differences between groups were compared using unpaired Student’s t test for each time point: *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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fig5: GPR174 deficiency in T reg cells limits the severity of EAE. (A) EAE was induced in 10-wk-old male wild-type or Gpr174−/Y littermate mice by injecting a MOG35–55 + CFA emulsion (s.c.) followed by pertussis toxin (i.v.). Mice were scored daily for disease symptoms; mean disease scores are shown and error bars indicate SEM. (B) The frequency of Foxp3+ T reg cells among total CD4+ T cells was determined in the indicated tissues 12 d after EAE induction in 10-wk-old male wild-type or Gpr174−/Y littermate mice by flow cytometry. (C) EAE was induced in a cohort of wild-type mice, and levels of LysoPS were measured by LC-MS/MS in the inguinal LN that drained the MOG + CFA emulsion (dotted lines) and in the spinal cord (solid lines) throughout the course of disease; n = 3–5. (B and C) Error bars show SD. (D) EAE was induced in 10-wk-old female Gpr174+/− or wild-type littermate mice as in A; error bars show SEM. (E and F) In Gpr174+/− or wild-type female mice heterozygous for an X-linked Foxp3-DTR allele, diphtheria toxin (DTx) was injected on days −10, −7, and −4. EAE was induced as in A on day 0. The ablation efficiency was assessed by analyzing the frequency of DTR-GFP+ cells among blood CD4+CD25+ T reg cells at the indicated time points (E); error bars show SD. Disease was scored daily after MOG immunization (F); n = 11; error bars show SEM. Data are representative of two (E and F) or three or more (A–D) independent experiments. Differences between groups were compared using unpaired Student’s t test for each time point: *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Mentions: Finally, given the constraining influence of GPR174 on T reg cell development and functionality, we examined whether GPR174 deficiency might protect mice from autoimmune pathology. To induce EAE, we administered myelin oligodendrocyte glycoprotein (MOG) peptide in CFA along with pertussis toxin. In this disease model, Th1 and Th17 cells drive CNS inflammation, whereas T reg cells can limit disease severity and promote the remission of symptoms (Stromnes and Goverman, 2006). Although the day of disease onset was unaffected, Gpr174−/Y male mice showed significantly reduced peak disease severity compared with wild-type littermates (Fig. 5 A). At day 12, a time point when Gpr174−/Y and wild-type mice showed a similar disease score, the frequency of Foxp3+ T reg cells was not significantly affected by GPR174 deficiency in the secondary lymphoid organs or spinal cord (Fig. 5 B); however, the frequency of CD103+ cells among T reg cells remained elevated in the draining LN at days 8–12 (not depicted). Moreover, levels of 16:0, 18:0, and 18:1 LysoPS did not appear to markedly change in the draining LN or spinal cord throughout the experiment (Fig. 5 C). These whole tissue analyses do not exclude the possibility that there are changes in other LysoPS isoforms (Blankman et al., 2013; Kamat et al., 2015) or local changes in interstitial LysoPS concentrations that affect cell behavior.

Bottom Line: In vivo, LysoPS was detected in lymphoid organ and spinal cord tissues and was abundant in the colon.This study provides evidence that a bioactive lipid, LysoPS, negatively influences T reg cell accumulation and activity through GPR174.As such, GPR174 antagonists might have therapeutic potential for promoting immune regulation in the context of autoimmune disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: Howard Hughes Medical Institute, Department of Microbiology and Immunology, and Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute, Department of Microbiology and Immunology, and Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143.

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Related in: MedlinePlus