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CD4(+)FoxP3(+) Regulatory T Cells from G alpha i2(-/-) Mice Are Functionally Active In Vitro, but Do Not Prevent Colitis
Örebro University, School of Health and Medical Sciences.ORCID iD: 0000-0001-5460-8888
2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e25073-Article in journal (Refereed) Published
Abstract [en]

Background: Mice deficient in the inhibitory G protein subunit G alpha i2 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 G alpha i2(-/-) (G alpha i2-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 G alpha i2(-/-) mice contained increased frequencies of Treg, whereas FoxP3 expression intensity was similar in G alpha i2(-/-) compared to G alpha i2(-/-) or G alpha i2(+/+) wild type (WT) mice. The frequency of CD4(+)FoxP3(+) T cells expressing CD103 was significantly increased in G alpha i2(-/-) 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 G alpha i2(-/-) 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 G alpha i2(-/-) CD4(+)FoxP3(+) regulatory T cells (WT-Treg and KO-Treg) was indistinguishable, but that T effector cells (CD4(+)25(-) T cells) from G alpha i2(-/-) mice were less readily suppressed than WT effectors (WT-Teff) by Treg from either source. However, neither WT nor G alpha i2(-/-) Treg was able to suppress colitis induced by adoptive transfer of G alpha i2(-/-) effector T cells (KO-Teff) to RAG2(-/-) recipients. The enhanced inflammatory activity of G alpha i2(-/-) effectors was accompanied by increased expression of an effector/memory T cell phenotype and increased cytokine secretion, especially IL-4, IL-6 and IFN-gamma. Conclusions: There is an increased frequency of G alpha i2(-/-) Treg in the colon, and they demonstrate no endogenous functional defect. However, G alpha i2(-/-) T effector cells are dramatically less susceptible to suppression in vitro, and in vivo, despite increased effective numbers of Treg, they cannot prevent disease.

Place, publisher, year, edition, pages
2011. Vol. 6, no 9, p. e25073-
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-20855DOI: 10.1371/journal.pone.0025073ISI: 000295265100048OAI: oai:DiVA.org:oru-20855DiVA, id: diva2:476143
Available from: 2012-01-11 Created: 2012-01-11 Last updated: 2017-12-08Bibliographically approved

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Hultgren Hörnquist, Elisabeth

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