Immune Regulatory Function of Tregs

Regulatory CD4+ T cells (Tregs) have become increasingly appreciated in their role of facilitating immunological tolerance during homeostasis and during the diseased state. A general understanding of the literature characterizes Tregs as key elements of the immune system involving in the suppression of immune responses against cancer or infectious diseases, as well as the prevention of autoimmune diseases. However, the immune regulatory role of Tregs goes beyond this simple suppressive function, since, for example, Tregs actively contribute to the maintenance of intestinal epithelial cell homeostasis by producing TGF-β, which in turn helps B cells produce IgA. Therefore, topics that were selected in this thematic issue cover the pleiotropic functions of Tregs during homeostasis and disease, which we hope will contextualize these cells within the broader immunological terrain. This thematic issue is meant to provide an overview of the contribution of Tregs during subclinical diseases or cancer dormancy as well as clinical diseases including cancer and autoimmunity. Authors were selected based on their research interests and accomplishments in the area of cellular immunology, with a focus on T cell biology. To this end, the contribution of Fabian Benencia of Ohio University, an expert on antigen presentation during the activation or suppression of T cells (Benencia et al., 2014), focuses on the role of Tregs in ovarian cancer (Singh et al., 2016), and outlines experimental approaches to impair their immunosuppressive function.

Paula Bos of Virginia Commonwealth University (VCU) is an expert on the interaction of Tregs with the tumor microenvironment. She investigated the role of Tregs during tumor progression during her postdoctoral training in the laboratory of Dr. Rudensky (Bos et al., 2013). In the review provided by Dr. Bos, we are introduced to non-classical functions of Tregs. Beyond the more classical role of Tregs as suppressors of immunity, these cells have also been shown to be contributors to tissue remodeling and repair, and have been demonstrated to exhibit immune-independent functions, such as angiogenesis. Dr. Bos discusses such alternative mechanisms by which Tregs may contribute to tumor progression (Bos, 2016).

Nejat Egilmez of the University of Louisville is an expert in the area of Th1 immune responses and modulation of Tregs during immunotherapy (Li et al., 2015). In their review, Li and Egilmez discuss the ontogeny of tumor-associated Tregs. The well-established and critical contribution of Tregs to immune suppression in the tumor microenvironment is discussed. The authors importantly consider that information regarding the origin and population dynamics of Tregs remains limited. The central question brought forward in this review is the relative contribution of thymic Tregs and peripheral Tregs to the total tumor Treg population, and the mechanisms underlying the prevalence of each population in tumors. Therefore, the ontogeny of tumor-associated Tregs is discussed in this review (Li and Egilmez, 2016).

B.J. Monzavi-Karbassi of the University of Arkansas for Medical Sciences is an expert in the area of cancer vaccines (Monzavi-Karbassi et al., 2007) whose work provides an insight into the role of Tregs during vaccination. In a contribution of original work, Monzavi-Karbassi et al. investigated the effect of modulation of the expression of tumor-associated antigens in influencing the immunogenicity of a cell-based vaccination strategy. Interestingly, they observed that crude tumor-secreted antigens activated Tregs and induced their suppressive potential. This suggests that tumor-associated antigens can be enriched using their glycan expression pattern to weaken immune suppression and to improve antitumor immune responses (Monzavi-Karbassi et al., 2016).

Masoud Manjili of VCU Massey Cancer Center is a tumor immunologist whose research program is focused on immunotherapy of breast cancer and targeting tumor dormancy while overcoming immune suppressor cells (Manjili, 2014; Payne et al., 2016). In their review, Manjili and Butler discuss the poorly understood concept of tumor cell dormancy in the context of immune-mediated maintenance, as well as escape and subsequent recurrence. Given this poorly defined nature of immune responses in the setting of tumor dormancy, the authors’ contribution provides a well-timed review of the literature related to the role of Tregs to the maintenance of tumor dormancy and/or recurrence (Manjili and Butler, 2016).

Kyle Payne of the Wistar Institute is an expert in the cellular crosstalk of the tumor immuno-environment, and modulation of T cell responses as well as immune suppressor cells (Payne et al., 2016; Payne et al., 2013). In his review, Dr. Payne discusses the crosstalk Tregs establish with myeloid cells in the tumor microenvironment, and also discusses the emerging appreciation of γδ-T cells as atypical regulators of antitumor immunity (Payne, 2016).

Qingguo Ruan is an expert in the field of immune regulation and the pathogenesis of autoimmune disease (Ruan et al., 2011). The original work by Wang and others from the laboratory of Dr. Ruan (Wang et al., 2016) investigates the requirement of the NF-κB family transcription factor, c-Rel, in the in vivo generation of peripherally induced Tregs. The data presented by the authors suggest that c-Rel may play distinct roles in regulating the development of peripherally induced Tregs within diverse tissue microenvironments (Wang et al., 2016).

The original work by Sznurkowska et al. investigates regulatory T cells in children with inflammatory bowel disease (IBD). The authors hypothesized that defective immune regulation leads to pathological immune responses directed against gut flora at the onset of IBD, therefore they describe a study which quantified Tregs in these patients in order to identify possible correlations between the presence of regulatory T cell and the pathology of IBD (Sznurkowska et al., 2016).

Anthony Vella of the University of Connecticut is an expert in the area of dual co-stimulation of T cells, and modulation of Tregs, both CD4+ and CD8+ Tregs (St Rose et al., 2013). Wang and Vella summarize the current knowledge on the roles of Tregs during cancer development, as well as the underlying cellular and molecular mechanisms in their review. They discuss the dual role of Tregs in functioning for the development, progression, and treatment of cancers, in which evidence is cited for their suppressive function against antitumor immunity, as well as the ability of Tregs to act directly on transformed epithelial cells to exert opposing effects during cancer development (Wang and Vella, 2016).

Xingxing Zang of the Albert Einstein College of Medicine is an expert in T cell biology and the mechanisms by which co-stimulation and co-inhibition regulate T cells (Zang et al., 2016). The review contributed from Dr. Zang’s laboratory by Liu et al. discusses the role of co-stimulatory and co-inhibitory signals in being key mechanistic contributors to the regulation of adaptive immunity, and, further, discusses the recent progress in delineating the roles of co-stimulatory and co-inhibitory signals in the context of Tregs (Liu et al., 2016).

Acknowledgments

This work was supported by the office of the Assistant Secretary of Defense for Health Affairs (USA) through the Breast Cancer Research Program under Award No. W81XWH-14-1-0087. Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Department of Defense.