The Role of Regulatory T Cells in Cancer

There has been an explosion of literature focusing on the role of regulatory T (Treg) cells in cancer immunity. It is becoming increasingly clear that Treg cells play an active and significant role in the progression of cancer, and have an important role in suppressing tumor-specific immunity. Thus, there is a clear rationale for developing clinical strategies to diminish their regulatory influences, with the ultimate goal of augmenting antitimor immunity. Therefore, manipulation of Treg cells represent new strategies for cancer treatment. In this Review, I will summarize and review the explosive recent studies demonstrating that Treg cells are increased in patients with malignancies and restoration of antitumor immunity in mice and humans by depletion or reduction of Treg cells. In addition, I will discuss both the prognostic value of Treg cells in tumor progression in tumor-bearing hosts and the rationale for strategies for therapeutic vaccination and immunotherapeutic targeting of Treg cells with drugs and microRNA

The Role of MicroRNAs in Regulatory T Cells and in the Immune Response

The discovery of microRNA (miRNA) is one of the major scientific breakthroughs in recent years and has revolutionized current cell biology and medical science. miRNAs are small (19~25nt) noncoding RNA molecules that post-transcriptionally regulate gene expression by targeting the 3' untranslated region (3'UTR) of specific messenger RNAs (mRNAs) for degradation of translation repression. Genetic ablation of the miRNA machinery, as well as loss or degradation of certain individual miRNAs, severely compromises immune development and response, and can lead to immune disorders. Several sophisticated regulatory mechanisms are used to maintain immune homeostasis. Regulatory T (Treg) cells are essential for maintaining peripheral tolerance, preventing autoimmune diseases and limiting chronic inflammatory diseases. Recent publications have provided compelling evidence that miRNAs are highly expressed in Treg cells, that the expression of Foxp3 is controlled by miRNAs and that a range of miRNAs are involved in the regulation of immunity. A large number of studies have reported links between alterations of miRNA homeostasis and pathological conditions such as cancer, cardiovascular disease and diabetes, as well as psychiatric and neurological diseases. Although it is still unclear how miRNA controls Treg cell development and function, recent studies certainly indicate that this topic will be the subject of further research. The specific circulating miRNA species may also be useful for the diagnosis, classification, prognosis of diseases and prediction of the therapeutic response. An explosive literature has focussed on the role of miRNA. In this review, I briefly summarize the current studies about the role of miRNAs in Treg cells and in the regulation of the innate and adaptive immune response. I also review the explosive current studies about clinical application of miRNA

Foxp3(+) regulatory T cells, Th17 effector cells, and cytokine environment in inflammatory bowel disease

Background: Inflammatory bowel disease (IBD) is thought to result from an aberrant immune response. Inflammation in IBD may be caused by the loss of homeostasis between CD4+ CD25high Foxp3+ regulatory cells (T reg) and proinflammatory Th17 cells. The aim of this study was to investigate T reg and Th17 cells in the peripheral blood and intestinal mucosa of IBD patients and to assess the mucosal cytokine environment. Methods: T reg and Th17 cells were measured in peripheral blood of 63 IBD patients and 28 controls by flow cytometry. Forkhead box p3 (Foxp3), interleukin (IL)-17a, IL-1β, IL-6, IL-21, IL-23, and transforming growth factor (TGF)-β mRNA were analyzed using real-time reverse transcription polymerase chain reaction in intestinal biopsies of 24 IBD and 18 control subjects. Results: A decrease in T reg and increase in Th17 cells was observed in the peripheral blood of IBD patients. When measured in the same patient and expressed as a ratio, a significant decrease in T reg/Th17 ratio was observed in IBD. Elevated expression of Foxp3, IL-17a, IL-1β, and IL-6 was observed in the mucosa of IBD patients, while TGF-β was only elevated in ulcerative colitis. Conclusion: IBD is associated with a reduced ratio of T reg to Th17 cells in peripheral blood and is characterized by a proinflammatory cytokine microenvironment, which supports the continued generation of Th17 cells.Nicola Eastaff-Leung, Nicholas Mabarrack, Angela Barbour, Adrian Cummins and Simon Barr

The recent thymic origin, differentiation and suppressive mechanism of regulatory T cells.

Regulatory T cells are a purported lineage of CD4⁺ cells that inhibit the proliferation and effector functions of other T cells to prevent the development of autoimmune disease. However, little is known about how they arise, their lifespan and their patterns of recirculation. Furthermore, the mechanisms through which they inhibit other T cells remain unclear. In order to address these issues, we investigated the relationship between regulatory T cells and recent thymic emigrants (RTE) which are newly formed T cells released into the periphery from the thymus. The CD25⁺ Foxp3⁺ regulatory T cell subset was found to be closely associated with RTE, and generated the CD25⁻ Foxp3⁺ T regulatory T cell subset by unidirectional differentiation. This process was exploited to mature flow sorted CD4⁺ CD25bright[bright in superscript]Foxp3⁺ T cells into CD25⁻ Foxp3⁺ T cells and determine that they retain their functional suppressive activity. The phenotype and physiology of the CD25⁺ Foxp3⁺ and CD25⁻ Foxp3⁺ regulatory T cell subsets were characterised and compared to conventional T cell subsets, revealing the differential expression of numerous key molecules. The high expression of CD62L and LFA-1 by CD25⁺ Foxp3⁺ regulatory T cells was consistent with both their relative enrichment within secondary lymphoid tissues and their sessile nature. The profile of adhesion molecules on the surface of CD25⁻ Foxp3⁺ cells suggested they may tend to localise to sites of inflammation other than the lamina propria, as they have a low expression of CD103 and CD62L, but high expression of LFA-1. However, CD25⁻ Foxp3⁺ regulatory T cells were found to selectively migrate into the intestinal mucosa, where they were enriched, and they also returned back to the thymus, suggesting they may constitute a tissue homing subset of regulatory T cells. We explored the mechanism of regulatory T cell suppression, and found that regulatory T cells condition APC to reduce their ability to activate other T cells. Following the application of this system to differential gene expression microarray analysis, we identified several putative molecular targets of regulation including 10 novel predicted serine/threonine kinases, a novel four point-1, ezrin, radixin and moesin domain containing signalling molecule, the E2F transcription factor 5, and a CD163-like molecule. Aging was found to negatively affect the productivity of the thymus, although it was found to be still generating new T cells into old age. While the number of thymocytes decreased with aging, the number of Foxp3⁺ cells in the thymus was unaffected, possibly their preferential recirculation back to the thymus. The size of the peripheral T cell pool decreased with aging, and the proportion of CD25⁺ Foxp3⁺ regulatory T cells among CD4+ T cells declined. However, the proportion of CD25⁻ Foxp3⁺ regulatory T cells increased with aging in the periphery. The conversion of CD25⁺ Foxp3⁺ regulatory T cells into CD25⁻ Foxp3⁺ T cells may compensate for the declining thymic output of CD25⁺ Foxp3⁺ regulatory T cells that occurs with aging, in order to maintain the regulatory T cell pool.Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 201

Recent thymic origin, differentiation, and turnover of regulatory T cells

Copyright © 2008 by Society for Leukocyte BiologyRegulatory CD4+ T cells (Treg) are essential to maintain self-tolerance. Release of natural Treg from the thymus is believed to commence soon after birth, but it is unclear how many are produced by "conversion" in the periphery, whether numbers are maintained after puberty by general homeostatic mechanisms that regulate lymphocyte numbers, or whether significant numbers are produced by the involuted thymus. To address the origin of Treg in normal adult rats, we focused on recent thymus emigrants (RTE). Approximately 30% of CD4+CD25+forkhead box p3 (Foxp3)+ Treg expressed markers associated with RTE. Following thymectomy, numbers of cells expressing these markers fell by 80% within 30 days. Furthermore, although only approximately 5% of CD4+ single-positive thymocytes expressed Foxp3 within 24 h after intrathymic injection of FITC, more than 30% of the labeled CD4+ RTE were Foxp3+, suggesting that some RTE may acquire Foxp3 in the periphery. Thus, some RTE may acquire Foxp3 rapidly after emigration from the thymus. Treg are dividing rapidly with apparent half-lives of approximately 18 days and approximately 7 days for the CD4+CD25+Foxp3+ and CD4+CD25-Foxp3+ subsets, respectively. The apparently slower turnover of CD4+CD25+Foxp3+ cells is a result of CD4+CD25+Foxp3+ --> CD4+CD25-Foxp3+ conversion, with no loss of regulatory function. Taken together, the data suggest that Treg in adults are relatively short-lived and that their numbers are maintained by rapid cell division and continuous replenishment from the thymus.Nicholas H. E. Mabarrack, Nicole L. Turner and Graham Mayrhofe