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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 intrinsically constrains T reg cell accumulation and CD103 expression. (A) Flow cytometry analysis of the percentage of dTomato+ cells in CD25− and CD25+ CD4 SP T reg thymocytes in Gpr174+/− female mice. Lines link measurements of populations from the same mouse; n = 8. (B and C) Flow cytometry analysis of the frequency of Foxp3+ CD4 SP or CD4+ T cells in 8-wk-old wild-type and Gpr174−/Y littermate male mice (B) and of the percentage of Foxp3+ CD4 SP or CD4+ T cells that express CD103 (surface) or Helios (intracellular; C); n = 7 or 9. Horizontal lines indicate the mean. (D) Flow cytometry analysis of mice reconstituted with mixed wild-type and Gpr174−/Y bone marrow. Lethally irradiated Ly5-2 mice (CD45.1+) were reconstituted with a mixture of bone marrow from wild-type Ly5-1/-2 F1 (CD45.1+CD45.2+) and Gpr174−/Y (Ly5-1, CD45.2+) mice. Radioresistant cells (Ly5-2, CD45.1+) were excluded, and the contribution of Gpr174−/Y-derived cells (Ly5-1) to the indicated cell subsets is shown; n = 4; error bars show SD. (E) The contribution of Gpr174−/Y-derived cells to the CD103+ T reg cell population is shown for mice reconstituted as in D, or with mixed bone marrow from wild-type Ly5-1/-2 F1 (CD45.1+CD45.2+) and wild-type mice (Ly5-1, CD45.2+) mice; n = 4. All data are representative of at least three independent experiments and were evaluated using paired (A, E) or unpaired (B–D) Student’s t test: *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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fig2: GPR174 intrinsically constrains T reg cell accumulation and CD103 expression. (A) Flow cytometry analysis of the percentage of dTomato+ cells in CD25− and CD25+ CD4 SP T reg thymocytes in Gpr174+/− female mice. Lines link measurements of populations from the same mouse; n = 8. (B and C) Flow cytometry analysis of the frequency of Foxp3+ CD4 SP or CD4+ T cells in 8-wk-old wild-type and Gpr174−/Y littermate male mice (B) and of the percentage of Foxp3+ CD4 SP or CD4+ T cells that express CD103 (surface) or Helios (intracellular; C); n = 7 or 9. Horizontal lines indicate the mean. (D) Flow cytometry analysis of mice reconstituted with mixed wild-type and Gpr174−/Y bone marrow. Lethally irradiated Ly5-2 mice (CD45.1+) were reconstituted with a mixture of bone marrow from wild-type Ly5-1/-2 F1 (CD45.1+CD45.2+) and Gpr174−/Y (Ly5-1, CD45.2+) mice. Radioresistant cells (Ly5-2, CD45.1+) were excluded, and the contribution of Gpr174−/Y-derived cells (Ly5-1) to the indicated cell subsets is shown; n = 4; error bars show SD. (E) The contribution of Gpr174−/Y-derived cells to the CD103+ T reg cell population is shown for mice reconstituted as in D, or with mixed bone marrow from wild-type Ly5-1/-2 F1 (CD45.1+CD45.2+) and wild-type mice (Ly5-1, CD45.2+) mice; n = 4. All data are representative of at least three independent experiments and were evaluated using paired (A, E) or unpaired (B–D) Student’s t test: *, P < 0.05; **, P < 0.01; ***, P < 0.001.

Mentions: Because T reg cells expressed high amounts of LysoPS receptors, we characterized the effects of GPR174 deficiency on these cells. Initially, we took advantage of the linkage of Gpr174 to the X chromosome, for which one copy is subject to random inactivation in female cells. Therefore, approximately half of the hematopoietic cells in female Gpr174+/− mice express the Gpr174−-dTomato allele. Intriguingly, we consistently detected an increased frequency of dTomato+ cells among CD25+ compared with CD25− CD4 SP thymocytes (Fig. 2 A), suggesting that the fitness of T reg cells might be greater when GPR174 is absent. To quantify T reg cell abundance in Gpr174−/Y mice, we measured Foxp3 expression in the thymus, secondary lymphoid organs, and colon lamina propria. The frequency of Gpr174−/Y Foxp3+ CD4 SP cells was significantly increased in the thymus, the site where most T reg cells develop, and in the colon lamina propria, where both thymus-derived and peripherally induced T reg cells can accumulate in microbiota-colonized mice (Fig. 2 B; Bollrath and Powrie, 2013). In contrast, T reg cell frequencies were unaffected in the spleen and LNs (Fig. 2 B), where extrinsic factors that include γc-cytokines govern the niche size. Therefore, GPR174 deficiency appeared to favor T reg cell accumulation in specific tissues.


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 intrinsically constrains T reg cell accumulation and CD103 expression. (A) Flow cytometry analysis of the percentage of dTomato+ cells in CD25− and CD25+ CD4 SP T reg thymocytes in Gpr174+/− female mice. Lines link measurements of populations from the same mouse; n = 8. (B and C) Flow cytometry analysis of the frequency of Foxp3+ CD4 SP or CD4+ T cells in 8-wk-old wild-type and Gpr174−/Y littermate male mice (B) and of the percentage of Foxp3+ CD4 SP or CD4+ T cells that express CD103 (surface) or Helios (intracellular; C); n = 7 or 9. Horizontal lines indicate the mean. (D) Flow cytometry analysis of mice reconstituted with mixed wild-type and Gpr174−/Y bone marrow. Lethally irradiated Ly5-2 mice (CD45.1+) were reconstituted with a mixture of bone marrow from wild-type Ly5-1/-2 F1 (CD45.1+CD45.2+) and Gpr174−/Y (Ly5-1, CD45.2+) mice. Radioresistant cells (Ly5-2, CD45.1+) were excluded, and the contribution of Gpr174−/Y-derived cells (Ly5-1) to the indicated cell subsets is shown; n = 4; error bars show SD. (E) The contribution of Gpr174−/Y-derived cells to the CD103+ T reg cell population is shown for mice reconstituted as in D, or with mixed bone marrow from wild-type Ly5-1/-2 F1 (CD45.1+CD45.2+) and wild-type mice (Ly5-1, CD45.2+) mice; n = 4. All data are representative of at least three independent experiments and were evaluated using paired (A, E) or unpaired (B–D) Student’s t test: *, P < 0.05; **, P < 0.01; ***, P < 0.001.
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fig2: GPR174 intrinsically constrains T reg cell accumulation and CD103 expression. (A) Flow cytometry analysis of the percentage of dTomato+ cells in CD25− and CD25+ CD4 SP T reg thymocytes in Gpr174+/− female mice. Lines link measurements of populations from the same mouse; n = 8. (B and C) Flow cytometry analysis of the frequency of Foxp3+ CD4 SP or CD4+ T cells in 8-wk-old wild-type and Gpr174−/Y littermate male mice (B) and of the percentage of Foxp3+ CD4 SP or CD4+ T cells that express CD103 (surface) or Helios (intracellular; C); n = 7 or 9. Horizontal lines indicate the mean. (D) Flow cytometry analysis of mice reconstituted with mixed wild-type and Gpr174−/Y bone marrow. Lethally irradiated Ly5-2 mice (CD45.1+) were reconstituted with a mixture of bone marrow from wild-type Ly5-1/-2 F1 (CD45.1+CD45.2+) and Gpr174−/Y (Ly5-1, CD45.2+) mice. Radioresistant cells (Ly5-2, CD45.1+) were excluded, and the contribution of Gpr174−/Y-derived cells (Ly5-1) to the indicated cell subsets is shown; n = 4; error bars show SD. (E) The contribution of Gpr174−/Y-derived cells to the CD103+ T reg cell population is shown for mice reconstituted as in D, or with mixed bone marrow from wild-type Ly5-1/-2 F1 (CD45.1+CD45.2+) and wild-type mice (Ly5-1, CD45.2+) mice; n = 4. All data are representative of at least three independent experiments and were evaluated using paired (A, E) or unpaired (B–D) Student’s t test: *, P < 0.05; **, P < 0.01; ***, P < 0.001.
Mentions: Because T reg cells expressed high amounts of LysoPS receptors, we characterized the effects of GPR174 deficiency on these cells. Initially, we took advantage of the linkage of Gpr174 to the X chromosome, for which one copy is subject to random inactivation in female cells. Therefore, approximately half of the hematopoietic cells in female Gpr174+/− mice express the Gpr174−-dTomato allele. Intriguingly, we consistently detected an increased frequency of dTomato+ cells among CD25+ compared with CD25− CD4 SP thymocytes (Fig. 2 A), suggesting that the fitness of T reg cells might be greater when GPR174 is absent. To quantify T reg cell abundance in Gpr174−/Y mice, we measured Foxp3 expression in the thymus, secondary lymphoid organs, and colon lamina propria. The frequency of Gpr174−/Y Foxp3+ CD4 SP cells was significantly increased in the thymus, the site where most T reg cells develop, and in the colon lamina propria, where both thymus-derived and peripherally induced T reg cells can accumulate in microbiota-colonized mice (Fig. 2 B; Bollrath and Powrie, 2013). In contrast, T reg cell frequencies were unaffected in the spleen and LNs (Fig. 2 B), where extrinsic factors that include γc-cytokines govern the niche size. Therefore, GPR174 deficiency appeared to favor T reg cell accumulation in specific tissues.

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.

Show MeSH
Related in: MedlinePlus