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In healthy adults, the immune system maintains a repertoire of T and B lymphocytes that recognize and eliminate infecting microorganisms and yet remain unresponsive toward the host's own cells and tissues. The goal of the Caton laboratory is to define the mechanisms by which B cells and T cells that "recognize" the body's own tissues and cells (autoreactive) are regulated and to understand how these processes fail and/or can be manipulated in autoimmune diseases like lupus and cancer.
To examine these questions the laboratory has analyzed immune response to influenza virus in great detail, and has generated transgenic mice that express a well-characterized antigen from influenza virus called HA, using a variety of promoters to direct HA expression in different cells and tissues. The researchers have shown that variations in the expression of HA in different transgenic mouse lineages can cause CD4+ T cells with identical specificity for a self-peptide either to be deleted (to varying degrees); to undergo selection to become CD4+ CD25+ regulatory T cells; or to become auto-aggressive, that is "attack" the body's own tissues and cells. The Caton laboratory has contributed to the considerable recent interest in the role that regulatory T cells, especially CD4+ CD25+ regulatory T cells, can play in preventing autoimmunity. They and others firmly established the existence of cell populations that prevent immune responses to host cells and tissues. The laboratory has also analyzed how autoreactive B cells that can recognize self-antigens are regulated and/or can become activated either by viral infection or spontaneously through failures to adequately regulate autoreactive CD4+ T cells. Studies in this system allow the Caton laboratory to define parameters that dictate how the immune system interacts with virus and self-antigens, and to develop approaches for preventing or augmenting these responses in different therapeutic settings.
The Caton Laboratory has been examining how Foxp3+CD4+ regulatory T (Treg) cells are instructed to undergo selection in response to self-peptides. In particular, how variations in the cell types and/or amounts with which peptides are expressed in different cell types was examined using transgenic mice expressing the influenza virus hemagglutinin (HA) under the control of several different promoters. Major conclusions from these studies were that regulatory T cell formation and deletion of autoreactive CD4+ T cells can take place simultaneously during thymic development, and that processes acting in the periphery can also contribute to CD25+ T cell repertoire formation. In recent studies his laboratory has been examining how TCR specificity directs regulatory T cell function in vivo.
The Caton laboratory previously used transgenic mouse systems to show that CD4+CD25+Foxp3+ Treg cells can undergo both thymic selection and peripheral expansion in response to self-peptides. These studies have shown that Treg cell formation is generally favored by interactions between CD4+ thymocytes and/or mature CD4+ T cells with low abundance self-peptides that are agonists for their T cell receptors (agonists are ligands for which the T cell receptor is highly specific). In addition, the extent to which Treg cell formation can be mediated by interactions with peptide ligands with which the TCR is only weakly crossreactive has been examined in vivo. Notably, weakly crossreactive ligands were able to induce deletion of autoreactive CD4+ thymocytes, but only an agonist self-peptide could induce Treg cell formartion (accompanied by deletion). These studies have shown that highly specific interactions with self-peptides are required for Treg cell formation in the thymus, and additional studies are being carried out with peripheral CD4+ T cells. In addition, the role of different cell types in expanding Treg cells has been examined, with mast cells being shown to be capable of mediating expansion of Treg cells in vivo.
The Caton laboratory has been using several models to analyze how Treg cells exert regulatory function in vivo. In one system, Treg cells that had been generated in response to a self-peptide were shown to be able to suppress immune response to an influenza virus expressing the same antigen as a viral peptide. Notably, these cells were able to suppress the immune response in the complex microenvironment of the lung, and involved the differentiation of the Treg cells into an effector phenotype characterized by expression of the transcription factor T-bet and the regulatory cytokine IL-10. Ongoing studies are analyzing the signals necessary to induce Treg cell differentiation, to determine the T cell receptor specificity requirements, and to examine whether long-term Treg memory cell formation can occur in vivo. An additional model under study is a mouse model of autoimmune inflammatory arthritis, where it has been shown that Tregs that are specific for the eliciting autoantigen fail to prevent disease, while addition of polyclonal Treg cells can inhibit disease development by disrupting Th-17 cell formation. The reasons that autoantigen-specific Tregs fail to mediate suppression in this system is under active investigation. A third model being analyzed is a mouse breast tumor model, where the extent to which Tregs can modulate the anti-tumor response and themselves differentiate to acquire novel phenotypes in the tumor microenvironment is being investigated.
The Caton laboratory has also been examining the mechanisms that determine how distinct cellular pathways can become activated and promote and/or control inflammatory processes. In the mouse model of inflammatory arthritis, interferon-gamma derived from autoreactive CD4+ T cells were found to induce the formation of inflammatory monocytes, which in turn induced the development of arthritogenic auotreactive CD4+ Th17 cells. As noted above, Treg cells can interfere with Th17 cell formation in these settings, and if they do so via their ability to interact with monocytes is being investigated. In other studies, how TCR affinity for self-peptides can determine the cellular pathways that can promote inflammation arthritis development (e.g. cytokine- versus B cell-mediated pathways) is being evaluated, and is also being examine in the mouse breast cancer model system.
The microscope in the image belonged to William E. Horner, M.D., a collaborator with Caspar Wistar, M.D., in the early 1800s.
Dr. Horner, a lecturer at the University of Pennsylvania, was a pioneer of the use of microscopes in anatomical and medical research. He authored Special Anatomy and Histology, a seminal text on the subject.