Enforced ROR (gamma)t expression in haematopoietic stem cells increases regulatory T cell number, which reduces immunoreactivity and attenuates hypersensitivity in vivo

Abstract

The retinoic acid receptor-related orphan receptor gammat (ROR(gamma)t) is a key transcription factor involved in the generation of T-helper 17 (Th17) cells, which mediate tissue inflammation and autoimmunity. However, recent studies indicated that less than half of all ROR(gamma)t(+) Talphabeta cells express IL-17, while the others are Foxp3(+) Talphabeta cells expressing IL-10. These observations raise questions regarding the role of ROR(gamma)t in the early differentiation process of T cells from haematopoietic stem cells. METHODS: To examine the role of RORyt in T cell differentiation, mice were reconstituted with ROR(gamma)t cDNA-transduced haematopoietic stem cells and the role of ROR(gamma)t in T cell differentiation was studied in a mouse bone marrow transplantation model in vivo. RESULTS: While the number of Th17 cells increased with the reduction in Thl cell number in transplanted mice, peripheral blood Foxp3(+) Talphabeta cell number also increased, which attenuated the severity of contact hypersensitivity on skin exposed to 2,4-dinitrofluorobenzene. The number of non-transduced Foxp3(+) regulatory T cells (Treg cells) also increased in these mice. CONCLUSION: These observations suggest that the enforced expression of ROR(gamma)t in haematopoietic stem cells induces differentiation of Thl7 cells and results in an increase in Foxp3(+) Treg cell number to limit self-tissue damage.

Part of CIRS Nexus · Curated by Lauren Lowenstein, The Biotoxin Lady

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