Conversion of Peripheral CD4+CD25− Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-β Induction of Transcription Factor <i>Foxp3 </i>WanJun Chen, Wenwen Jin, Neil J. Hardegen et al.|The Journal of Experimental Medicine|2003 CD4+CD25+ regulatory T cells (Treg) are instrumental in the maintenance of immunological tolerance. One critical question is whether Treg can only be generated in the thymus or can differentiate from peripheral CD4+CD25- naive T cells. In this paper, we present novel evidence that conversion of naive peripheral CD4+CD25- T cells into anergic/suppressor cells that are CD25+, CD45RB-/low and intracellular CTLA-4+ can be achieved through costimulation with T cell receptors (TCRs) and transforming growth factor beta (TGF-beta). Although transcription factor Foxp3 has been shown recently to be associated with the development of Treg, the physiological inducers for Foxp3 gene expression remain a mystery. TGF-beta induced Foxp3 gene expression in TCR-challenged CD4+CD25- naive T cells, which mediated their transition toward a regulatory T cell phenotype with potent immunosuppressive potential. These converted anergic/suppressor cells are not only unresponsive to TCR stimulation and produce neither T helper cell 1 nor T helper cell 2 cytokines but they also express TGF-beta and inhibit normal T cell proliferation in vitro. More importantly, in an ovalbumin peptide TCR transgenic adoptive transfer model, TGF-beta-converted transgenic CD4+CD25+ suppressor cells proliferated in response to immunization and inhibited antigen-specific naive CD4+ T cell expansion in vivo. Finally, in a murine asthma model, coadministration of these TGF-beta-induced suppressor T cells prevented house dust mite-induced allergic pathogenesis in lungs.
Transforming growth factor-β induces development of the TH17 lineageTransforming growth factor type beta induces monocyte chemotaxis and growth factor production.Sharon M. Wahl, D A Hunt, Lalage M. Wakefield et al.|Proceedings of the National Academy of Sciences|1987 Recent studies have focused on the potential role of transforming growth factor type beta (TGF-beta) as an immunoregulatory peptide. In this context, we demonstrate that TGF-beta is a potent chemoattractant for human peripheral blood monocytes. At concentrations from 0.1 to 10 pg/ml, TGF-beta induces directed monocyte migration in vitro. Consistent with this observation is the expression of high-affinity TGF-beta receptors on the monocytes with a Kd of 1-10 pM. At higher concentrations of TGF-beta (greater than or equal to 1 ng/ml), monocytes are stimulated to generate biologically active mediator(s) that enhance fibroblast growth. Gene expression for one of these growth factors, interleukin 1, is induced in monocytes within hours after exposure to TGF-beta. Thus, TGF-beta may provide an important signal for monocyte recruitment and for regulation of their synthesis of mediators of fibroblast growth and activity in wound healing.
Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory responseN-formylmethionyl peptides as chemoattractants for leucocytes.E Schiffmann, Barbara Corcoran, Sharon M. Wahl|Proceedings of the National Academy of Sciences|1975 Leucocytes such as neutrophils are attracted by N-formylmethionine, but not by methionine. Di- and tripeptides containing formylmethionine are strong attractants for both neutrophils and macrophages, whereas the corresponding nonacylated compounds are not chemotactic. The formylated peptides may be related to an incompletely characterized chemotactic material normally produced by bacteria which attract the same animal cells.