Ethan M. Shevach, M.D.

Chief, Cellular Immunology Section

Description of Research Program

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 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 10 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 which co-express CD25 which are capable of not only suppressing 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.

Recently, we have established an in vitro model system that mimics the function of these cells in vivo. The CD4+CD25+ population can readily suppress polyclonal and antigen-specific responses by a novel cytokine-independent, cell contact-dependent mechanism. The antigen specificity and precise mechanisms of suppression utilized by the CD4+CD25+ cells are the subjects of ongoing investigations.

While regulatory cells play a major role in preventing the induction of autoimmune disease, cytokines appear to be the major mediators that are responsible for the destruction of the involved organ. A second focus of our studies is the role of cytokine networks bridging the innate and acquired immune systems in the pathogenesis of organ-specific autoimmunity—particularly experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis.

Inflammatory immune responses are primarily mediated by CD4+ Th1 T cells, which produce interferon-gamma (IFN), while CD4+ Th2 populations, which produce IL-4, mediate antibody responses but not organ-specific tissue destruction. However, we have recently demonstrated that IFN is not required for disease pathogenesis, but that it may actually exert a profound protective effect. The protective effect of IFN is mediated by its capacity to regulate the production of certain T cell-derived chemokines that mediate migration of neutrophils and macrophages into the target organ, thus facilitating exacerbation of disease. In contrast to IFN, IL-12 was shown to be essential for the induction of both experimental EAE and collagen-induced arthritis.

We have also characterized a unique CD4+ T lymphocyte which is capable of producing IL-10, but whose IL-10 producing capacity is tonically suppressed by the constitutive production of IL-12. This cell population may play a unique role in the normal homeostatic processes which regulate the susceptibility of an individual animal to autoimmune disease. Our goals for the future include the design of several therapeutic protocols for the manipulation of cytokine/chemokine networks in autoimmunity that will be aimed at inhibiting not only the induction of disease, but also the modulation of established disease.

Purified CD4+CD25+ T cells inhibit the induction of gastritis induced by autoantigen-specific T cells.

1. 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
2. Gastric mucosa of nu/nu mouse which received 5X10⁶ TXA-23 cells and 50X10⁶ normal spleen cells
3. Gastric mucosa of nu/nu mouse which received 5X10⁶ TXA23 cells and 1x10⁶ purified CD4+CD25+ T cells

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.

Awards

Distinguished Service Award (American Association of Immunologists), Distinguished Alumnus Award (Boston University School of Medicine).

Memberships

• American Association of Immunologists
• American Society for Clinical Investigation
• Association of American Physicians

Editorial Boards

• Blood
• The Journal of Immunological Methods
• Journal of Biomedical Science
• Cellular Immunology (Editor-in-Chief)
• Current Protocols in Immunology
• Life Sciences

Selected Publications

(View list in PubMed.)

Mendel I, Shevach EM. Activated T cells express the OX40 ligand: requirements for induction and costimulatory function.Immunology. 2006 Feb;117(2):196-204.

Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood. 2006 May 15;107(10):3925-32. Epub 2006 Jan 17.

Brinster C, Shevach EM. Bone marrow-derived dendritic cells reverse the anergic state of CD4+CD25+ T cells without reversing their suppressive function. J Immunol. 2005 Dec 1;175(11):7332-40.

DiPaolo RJ, Glass DD, Bijwaard KE, Shevach EM. CD4+CD25+ T cells prevent the development of organ-specific autoimmune disease by inhibiting the differentiation of autoreactive effector T cells. J Immunol. 2005 Dec 1;175(11):7135-42.

Smeltz RB, Chen J, Shevach EM. Transforming growth factor-beta1 enhances the interferon-gamma-dependent, interleukin-12-independent pathway of T helper 1 cell differentiation. Immunology. 2005 Apr;114(4):484-92.

Thornton AM, Donovan EE, Piccirillo CA, Shevach EM. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol. 2004 Jun 1;172(11):6519-23.

Special Interest Groups
Immunology

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