Ethan Menahem Shevach, M.D.
Cellular Immunology Section
4 Memorial Drive, Room 228B
Bethesda, MD 20814
It is widely accepted that the development of autoimmune disease involves a breakdown in the mechanisms that control self versus non-self discrimination. The primary mechanism that leads to tolerance to self-antigens is thymic deletion of autoreactive T cells. However, some autoreactive T cells may escape thymic deletion or recognize antigens expressed only extrathymically. T-cell anergy and T-cell indifference/ignorance have been proposed as the primary mechanisms used to control these potentially harmful populations; however, these passive mechanisms for self-tolerance may not be sufficient to completely control potentially pathogenic cells. Evidence has accumulated over the past 15 years for an active mechanism of immune suppression in which a distinct subset of cells suppresses the activation of autoreactive T cells that have escaped passive mechanisms of tolerance induction.
Our major goal is to further the understanding of the mechanism of action of these regulatory cells in preventing autoimmunity. We have identified a unique population of regulatory CD4+ T cells that co-express CD25, which are capable of suppressing not only the induction of autoimmune disease in vivo, but also the disease induced by passive transfer of cloned autoantigen-specific effector cells (see figure below). These CD4+CD25+ T cells appear to be members of a unique lineage of cells that acquire CD25 expression during differentiation in the thymus and express the transcription factor Foxp3.
The major focus of the Cellular Immunology Section over the past decade has been furthering our understanding of the function of this unique, minor (approximately 10 percent), subpopulation of CD4+ T cells that express the transcription factor Foxp3. This population of cells has been termed regulatory T cells (Treg), although their primary function is suppression of immune responses. Our group was one of the first in the world to realize the importance of Treg, and we performed many of the initial studies that described their phenotype and function. The study of Tregs is now one of the most active areas of research in basic and clinical immunology. It was originally assumed that Tregs were a dedicated lineage of cells that developed only from thymic precursors, but more recent studies have clearly documented that Foxp3+ T cells also develop from conventional T cells (Tconv) in extra-thymic peripheral sites. The relative importance of thymic-derived (tTreg) and peripherally induced (iTreg) Tregs is unknown. Over the past six years, we have broadened the scope of our studies to include studies on human Tregs from both healthy donors and patients with autoimmune disease.
Four major areas are under study:
- We are are attempting to dissect the phenotypic and functional differences between tTreg and iTreg. We developed a novel antibody that identified the transcription factor Helios, a member of the Ikaros gene family. Expression of Heliosappears primarily to mark tTreg in both mouse and man. However, the function of Helios remains unknown, and it remains controversial whether the lack of Helios expression is a valid marker of the iTreg population. We have developed the necessary genetic models to address both of these major questions.
- We were partners on a collaborative Gates Grand Challenge Grant to investigate the role of Tregs in chronic viral infection, specifically infection of mice with chronic lymphocytic meningitis virus (LCMV). This study opened up a new and novel area of study in the group. LCMV infection had a profound effect on Treg functions. Interestingly, the effects of LCMV on Treg were mediated indirectly by viral modification of endogenous retroviral gene expression. The effects of chronic viral infection, those mediated both directly on Tregs and indirectly on endogenous retroviruses, are being vigorously pursued.
- We have developed rapid assays for the function of Treg in normal, immunocompetent mice. We have demonstrated that polyclonal Treg and antigen-specific iTreg behave differently in this model system. Our goal in these studies is to determine the target cell for Treg suppression and to dissect the molecular partners and mechanisms used by Tregs in vivo. We have discovered that Tregs express a unique cell surface receptor, GARP or LRRC32, which is specific for latent TGF-β. The contribution of TGF-β to Treg suppressor activity remains controversial, and TGF-β also plays a prominent role in Treg and Th17 induction. We are developing the necessary genetic tools to carefully differentiate between the functions of cell surface and secreted TGF-β in multiple immune models.
- We also are studying human Tregs (hTregs) and have developed a number of in vitro assays that use a hybrid system to measure hTreg function with mouse T responder cells and mouse dendritic cells (DCs). In this model, the human Tregs target mouse DCs. We are in the process of screening large panels of monoclonal antibodies (mAbs) to human Tregs to identify reagents that enhance or reverse Treg suppression in these assays. The molecular targets for these mAbs will be characterized. We have used RNA-Seq technology to identify genes uniquely expressed in human Tregs and are now validating the importance of these genes in Treg function. Our major goal in these studies is to develop novel biologics that can be used therapeutically in the clinic to modulate Treg function.
Purified CD4+CD25+ T cells inhibit the induction of gastritis induced by autoantigen-specific T cells.
- Gastric mucosa of nu/nu mouse injected with 5X106 TXA-23 cells which are specific for an epitope on the H/K ATPase of the gastric parietal cell
- Gastric mucosa of nu/nu mouse which received 5X106 TXA-23 cells and 50X106 normal spleen cells
- Gastric mucosa of nu/nu mouse which received 5X106 TXA23 cells and 1x106 purified CD4+CD25+ T cells
The research efforts of the Cellular Immunology Section are focused in the area of immune regulation in the pathogenesis and treatment of organ-specific autoimmune disease. It is widely accepted that the development of autoimmune disease involves a break
The severe gastritis and parietal cell destruction seen in panel A is markedly inhibited when normal spleen cells containing CD4+CD25+ cells (B) or purified CD4+CD25+ cells (C) are co-injected with the pathogenic Th1 clone.
Dr. Shevach received his M.D. from Boston University in 1967. Following clinical training, he joined the Laboratory of Immunology as a senior staff fellow in 1972, was appointed a senior investigator in 1973, and became a section chief in 1987. Dr. Shevach served as editor-in-chief of the Journal of Immunology from 1987 to 1992 and editor-in-chief of Cellular Immunology from 1996 to 2007. He received the 2004 William B. Coley Award for Distinguished Research in Basic and Tumor Immunology.
Distinguished Service Award (The American Association of Immunologists), Distinguished Alumnus Award (Boston University School of Medicine).
- The American Association of Immunologists
- American Society for Clinical Investigation
- Association of American Physicians
- The Journal of Immunological Methods
- Journal of Biomedical Science
- Journal of Experimental Medicine
- Current Protocols in Immunology
- Human Immunology
Special Interest Groups
Gangaplara A, Martens C, Dahlstrom E, Metidji A, Gokhale AS, Glass DD, Lopez-Ocasio M, Baur R, Kanakabandi K, Porcella SF, Shevach EM. Type I interferon signaling attenuates regulatory T cell function in viral infection and in the tumor microenvironment. PLoS Pathog. 2018;14(4):e1006985.
Thornton AM, Lu J, Korty PE, Kim YC, Martens C, Sun PD, Shevach EM. Helios<sup>+</sup> and Helios<sup>-</sup> Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires. Eur J Immunol. 2019;49(3):398-412.
Akkaya B, Oya Y, Akkaya M, Al Souz J, Holstein AH, Kamenyeva O, Kabat J, Matsumura R, Dorward DW, Glass DD, Shevach EM. Regulatory T cells mediate specific suppression by depleting peptide-MHC class II from dendritic cells. Nat Immunol. 2019;20(2):218-231.
Sebastian M, Lopez-Ocasio M, Metidji A, Rieder SA, Shevach EM, Thornton AM. Helios Controls a Limited Subset of Regulatory T Cell Functions. J Immunol. 2016;196(1):144-55.
Holt MP, Punkosdy GA, Glass DD, Shevach EM. TCR Signaling and CD28/CTLA-4 Signaling Cooperatively Modulate T Regulatory Cell Homeostasis. J Immunol. 2017;198(4):1503-1511.
Related Scientific Focus Areas
This page was last updated on August 14th, 2019