Scientists from the Walter and Eliza Hall Institute have identified the key immune cell population responsible for regulating the body’s immune response.
The finding could have wide-ranging repercussions for the treatment of autoimmune diseases, organ transplantation and cancer, and change how the efficacy of newly developed drugs is measured.
The discovery was made by Dr Erika Cretney, Dr Axel Kallies and Dr Stephen Nutt from the institute’s Molecular Immunology division. It centred on a population of immune cells called regulatory T cells.
Regulatory T cells (T-regs) are responsible for limiting the immune response. Disorders that decrease T-reg activity can lead to autoimmune disorders such as type 1 diabetes or coeliac disease, while increased T-reg activity can suppress the immune system when it should be actively killing cancerous or infected cells.
Dr Kallies said the research team had used molecular signatures to identify which cells within the regulatory T cell population were responsible for suppressing immune responses.
“It turns out that the bulk of cells which are classified as regulatory T cells may not do much,” Dr Kallies said. “In this study we have identified a distinct group of effector regulatory T cells, or ‘active T-regs’, which are the key drivers of immune response regulation.”
Dr Nutt said the research had implications for clinical trial outcomes.
“Researchers often measure regulatory T cell numbers in clinical trials as a parameter for establishing whether there has been a positive immune response,” Dr Nutt said. “We have shown that the absolute number of regulatory T cells isn’t as important as the presence of this particular active regulatory T cell population.”
Dr Nutt said the research showed that mice without active T-reg cell populations developed severe autoimmune inflammatory bowel disease, which is fatal.
“Not having this T cell population in the gut causes the immune response to go into overdrive and attack the body’s own cells,” he said. “A lack of the factor that is needed to generate active T-reg cells has also been implicated in human genome-wide studies of Crohn’s disease. So it would seem that this cell population is strongly linked to the development of autoimmunity.”
Dr Cretney said that re-defining the active subset of the T-reg population would give researchers the ability to develop new ways to increase or block their activity in the body. “The next step for my research is to look at the function of this active T-reg population in autoimmunity and in cancer.”
Dr Kallies said that for these reasons, there was a lot of excitement in the medical community about regulatory T cells. “Clinicians have shown that regulatory T cell activity impacts on many therapies,” he said. “Many research teams are trying to manipulate and expand these cells for therapeutic use. Our finding will transform the way that researchers look at immune responses and open new avenues for treating diseases such as autoimmunity and cancer.”
The research appears on the cover of today’s edition of Nature Immunology. It was supported by the National Health and Medical Research Council, the Australian Research Council and Pfizer Australia.
cancer.molecularblogs.com
Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-β receptor II (TGFβR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGFβR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-β) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFβR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFβR2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (αSMA)] through elevation of TGF-β1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFβR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-β1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-β1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-β signaling to tumor promotion by tumor stromal cells. Cancer Res; 71(4); 1272–81. 2011 AACR. cancerres.aacrjournals.org
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