CD4+FoxP3+ regulatory T cells from Gαi2-/- mice are functionally active in vitro, but do not prevent colitis.
BACKGROUND: Mice deficient in the inhibitory G protein subunit Gαi2 spontaneously develop a T helper 1 dominated colitis. We examined whether a defect in CD4(+)FoxP3(+) regulatory T cells (Treg) underpins the pathogenesis of colitis in the Gαi2(-/-) (Gαi2-deficient) colitis model. METHODOLOGY/PRINCI...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3178583?pdf=render |
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| author | Yu-Yuan C Götlind Sukanya Raghavan Paul W Bland Elisabeth Hultgren Hörnquist |
| author_facet | Yu-Yuan C Götlind Sukanya Raghavan Paul W Bland Elisabeth Hultgren Hörnquist |
| author_sort | Yu-Yuan C Götlind |
| collection | DOAJ |
| description | BACKGROUND: Mice deficient in the inhibitory G protein subunit Gαi2 spontaneously develop a T helper 1 dominated colitis. We examined whether a defect in CD4(+)FoxP3(+) regulatory T cells (Treg) underpins the pathogenesis of colitis in the Gαi2(-/-) (Gαi2-deficient) colitis model. METHODOLOGY/PRINCIPAL FINDINGS: Using flow cytometry, we found that thymus and colonic lamina propria, but not spleen and mesenteric lymph nodes, of colitic Gαi2(-/-) mice contained increased frequencies of Treg, whereas FoxP3 expression intensity was similar in Gαi2(-/-) compared to Gαi2(+/-) or Gαi2(+/+) wild type (WT) mice. The frequency of CD4(+)FoxP3(+) T cells expressing CD103 was significantly increased in Gαi2(-/-) compared to WT mice. Treg in colons from WT mice clustered in the T cell areas of colonic lymphoid patches (CLP), with relatively few Treg in the lamina propria, as demonstrated by immunohistochemistry. In Gαi2(-/-) mice, CLP were not observed but lamina propria Treg were increased in number and frequency within the CD4(+) infiltrate, compared to WT mice. Using an in vitro co-culture system and flow cytometric analysis of cell division we could demonstrate that the in vitro suppressive function of WT and Gαi2(-/-) CD4(+)FoxP3(+) regulatory T cells (WT-Treg and KO-Treg) was indistinguishable, but that T effector cells (CD4(+)25(-) T cells) from Gαi2(-/-) mice were less readily suppressed than WT effectors (WT-Teff) by Treg from either source. However, neither WT nor Gαi2(-/-) Treg was able to suppress colitis induced by adoptive transfer of Gαi2(-/-) effector T cells (KO-Teff) to RAG2(-/-) recipients. The enhanced inflammatory activity of Gαi2(-/-) effectors was accompanied by increased expression of an effector/memory T cell phenotype and increased cytokine secretion, especially IL-4, IL-6 and IFN-γ. CONCLUSIONS: There is an increased frequency of Gαi2(-/-) Treg in the colon, and they demonstrate no endogenous functional defect. However, Gαi2(-/-) T effector cells are dramatically less susceptible to suppression in vitro, and in vivo, despite increased effective numbers of Treg, they cannot prevent disease. |
| first_indexed | 2024-12-14T13:46:15Z |
| format | Article |
| id | doaj.art-744dcb1b0c9448fd9b23e7ab62dcfa13 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T13:46:15Z |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-744dcb1b0c9448fd9b23e7ab62dcfa132022-12-21T22:59:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0169e2507310.1371/journal.pone.0025073CD4+FoxP3+ regulatory T cells from Gαi2-/- mice are functionally active in vitro, but do not prevent colitis.Yu-Yuan C GötlindSukanya RaghavanPaul W BlandElisabeth Hultgren HörnquistBACKGROUND: Mice deficient in the inhibitory G protein subunit Gαi2 spontaneously develop a T helper 1 dominated colitis. We examined whether a defect in CD4(+)FoxP3(+) regulatory T cells (Treg) underpins the pathogenesis of colitis in the Gαi2(-/-) (Gαi2-deficient) colitis model. METHODOLOGY/PRINCIPAL FINDINGS: Using flow cytometry, we found that thymus and colonic lamina propria, but not spleen and mesenteric lymph nodes, of colitic Gαi2(-/-) mice contained increased frequencies of Treg, whereas FoxP3 expression intensity was similar in Gαi2(-/-) compared to Gαi2(+/-) or Gαi2(+/+) wild type (WT) mice. The frequency of CD4(+)FoxP3(+) T cells expressing CD103 was significantly increased in Gαi2(-/-) compared to WT mice. Treg in colons from WT mice clustered in the T cell areas of colonic lymphoid patches (CLP), with relatively few Treg in the lamina propria, as demonstrated by immunohistochemistry. In Gαi2(-/-) mice, CLP were not observed but lamina propria Treg were increased in number and frequency within the CD4(+) infiltrate, compared to WT mice. Using an in vitro co-culture system and flow cytometric analysis of cell division we could demonstrate that the in vitro suppressive function of WT and Gαi2(-/-) CD4(+)FoxP3(+) regulatory T cells (WT-Treg and KO-Treg) was indistinguishable, but that T effector cells (CD4(+)25(-) T cells) from Gαi2(-/-) mice were less readily suppressed than WT effectors (WT-Teff) by Treg from either source. However, neither WT nor Gαi2(-/-) Treg was able to suppress colitis induced by adoptive transfer of Gαi2(-/-) effector T cells (KO-Teff) to RAG2(-/-) recipients. The enhanced inflammatory activity of Gαi2(-/-) effectors was accompanied by increased expression of an effector/memory T cell phenotype and increased cytokine secretion, especially IL-4, IL-6 and IFN-γ. CONCLUSIONS: There is an increased frequency of Gαi2(-/-) Treg in the colon, and they demonstrate no endogenous functional defect. However, Gαi2(-/-) T effector cells are dramatically less susceptible to suppression in vitro, and in vivo, despite increased effective numbers of Treg, they cannot prevent disease.http://europepmc.org/articles/PMC3178583?pdf=render |
| spellingShingle | Yu-Yuan C Götlind Sukanya Raghavan Paul W Bland Elisabeth Hultgren Hörnquist CD4+FoxP3+ regulatory T cells from Gαi2-/- mice are functionally active in vitro, but do not prevent colitis. PLoS ONE |
| title | CD4+FoxP3+ regulatory T cells from Gαi2-/- mice are functionally active in vitro, but do not prevent colitis. |
| title_full | CD4+FoxP3+ regulatory T cells from Gαi2-/- mice are functionally active in vitro, but do not prevent colitis. |
| title_fullStr | CD4+FoxP3+ regulatory T cells from Gαi2-/- mice are functionally active in vitro, but do not prevent colitis. |
| title_full_unstemmed | CD4+FoxP3+ regulatory T cells from Gαi2-/- mice are functionally active in vitro, but do not prevent colitis. |
| title_short | CD4+FoxP3+ regulatory T cells from Gαi2-/- mice are functionally active in vitro, but do not prevent colitis. |
| title_sort | cd4 foxp3 regulatory t cells from gαi2 mice are functionally active in vitro but do not prevent colitis |
| url | http://europepmc.org/articles/PMC3178583?pdf=render |
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