Faculty Bibliography

The control of peripheral lymphocyte numbers is a fundamental aspect of the immune system. Regulatory T cells are involved in the suppression of autoimmune, antitumor, allergic, and other inflammatory responses, as well as in facilitating graft acceptance. In this paper, we discuss whether the control of homeostatic proliferation is another facet of the immune system that is controlled by regulatory T cells. A review of the published data connecting regulatory T cells with the control of homeostatic proliferation indicates that several key questions remain open. One of these relates to the stage at which regulatory T cells could play a role (i.e., T-cell proliferation vs. survival)

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the CNS initiated by autoreactive CD4(+) T cells. EAE classically presents with a progressive ascending paralysis and is a model of multiple sclerosis that recapitulates some aspects of the disease. In this report we describe a mouse strain that spontaneously develops a severe, nonclassical form of EAE with 100% incidence. The distinct clinical phenotype is marked initially by a slight head tilt, progressing to a severe head tilt, spinning, or a rotatory motion. Classical EAE spontaneously occurs in myelin basic protein (MBP)-specific TCR transgenic RAG-1(-/-) mice (referred to as T/R(-)), whereas nonclassical EAE spontaneously occurs in T/R(-) IFN-gamma(-/-) mice (T/R(-)gamma(-)). Thus, the TCR recognizes the same Ag (MBP) and uses identical TCR in both cases. The cellular infiltrate in nonclassical EAE is predominantly found in the brainstem and cerebellum, with very little inflammation in the spinal cord, which is primarily affected in classical disease. Importantly, depending on the genetic makeup and priming conditions of the MBP-specific T cells, nonclassical disease can occur in the presence of an inflammatory infiltrate with eosinophilic, neutrophilic, or monocytic characteristics. Finally, we believe that nonclassical spontaneous EAE could be a useful model for the study of some characteristics of multiple sclerosis not observed in classical EAE, such as the inflammatory responses in the brainstem and cerebellum that can cause vertigo.

Naturally occurring CD4(+) regulatory T cells are generally identified through their expression of CD25. However, in several experimental systems considerable T(reg) activity has been observed in the CD4(+)CD25(-) fraction. Upon adoptive transfer, the expression of CD25 in donor-derived cells is not stable, with CD4(+)CD25(+) cells appearing in CD4(+)CD25(-) T cell-injected animals and vice versa. We show in this study that CD25(+) cells arising from donor CD25(-) cells upon homeostatic proliferation in recipient mice express markers of freshly isolated T(reg) cells, display an anergic state, and suppress the proliferation of other cells in vitro. The maintenance of CD25 expression by CD4(+)CD25(+) cells depends on IL-2 secreted by cotransferred CD4(+)CD25(-) or by Ag-stimulated T cells in peripheral lymphoid organs

T cell receptor transgenic mice have been a valuable tool in the study of the immune system, from development to selection to tolerance or pathogenesis. In this manuscript we review the T cell receptor transgenic mouse lines with specificity for self antigens that have been reported before August 2003. Many such lines have been generated, which have been instrumental in our understanding of, among other aspects, the role regulatory T cells in preventing autoimmunity, the role of microbes in modifying its outcome, the influence of the genetic background, the importance of regional differences in self-antigen concentration, and the importance of differences in antigen deposition between different tissues

Atopic diseases are characterized by Th2 and IgE responses to common environmental and food antigens. In vivo, IgE production depends on interactions between allergen-specific B lymphocytes and Th2 lymphocytes. IgE levels are extremely low in normal individuals, suggesting that IgE production is under strong regulation. One of the reasons behind the lack of atopy in healthy individuals is the activity of regulatory T cells, which prevent naive T helper cell precursors from acquiring a differentiated Th2 phenotype. In addition to naturally occurring regulatory T cells, atopy can be prevented by allergen-specific tolerant/regulatory cells induced through mucosal stimulation, and by mechanisms that directly suppress Iepsilon sterile transcript production on activated B lymphocytes. This article reviews the recent progress on thymic-derived as well as peripherally induced regulatory T cells as they relate to atopy. The latter discussion also includes regulatory T cells that arise through immunotherapy

Following immunization with Plasmodium yoelii sporozoites, the CD8(+) T cell population specific for the SYVPSAEQI epitope expressed in sporozoite and liver stages of this malaria parasite revealed the existence of a short term Ag presentation process that translated into a single clonal burst. Further expansion of this CD8(+) T cell population in conditions of sustained Ag exposure and additional supply of naive cells was inhibited by regulatory mechanisms that were developed as early as 24-48 h after priming. Studies using mouse models for Plasmodium or influenza virus infections revealed that this mechanism is Ag specific and is mediated by activated CD8(+) T cells that inhibit the priming of naive cells. This interference of the priming of naive cells appeared to result from limited access to Ag-presenting dendritic cells, which become disabled or are eliminated after contact with activated cells. Thus, concomitantly with the development of their effector antimicrobial capacity, CD8(+) T cells also acquire a self-regulatory role that is likely to represent one of the earliest mechanisms induced in the course of an immune response and that limits the magnitude of the early expansion of CD8(+) T lymphocytes reactive to microorganisms

Multiple sclerosis (MS) is a devastating neuroinflammatory disorder of the central nervous system (CNS) in which T cells that are reactive with major components of myelin sheaths have a central role. The receptor for advanced glycation end products (RAGE) is present on T cells, mononuclear phagocytes and endothelium. Its pro-inflammatory ligands, S100-calgranulins, are upregulated in MS and in the related rodent model, experimental autoimmune encephalomyelitis (EAE). Blockade of RAGE suppressed EAE when disease was induced by myelin basic protein (MBP) peptide or encephalitogenic T cells, or when EAE occurred spontaneously in T-cell receptor (TCR)-transgenic mice devoid of endogenous TCR-alpha and TCR-beta chains. Inhibition of RAGE markedly decreased infiltration of the CNS by immune and inflammatory cells. Transgenic mice with targeted overexpression of dominant-negative RAGE in CD4+ T cells were resistant to MBP-induced EAE. These data reinforce the importance of RAGE-ligand interactions in modulating properties of CD4+ T cells that infiltrate the CNS

Research in Juan's laboratory focuses on the pathogenesis of T cell mediated diseases, investigating in particular the role of regulatory T cells in spontaneous experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, and the control of exacerbated IgE responses, such as the ones that occur in atopic individuals

CD4+ regulatory T cells (Treg) play an indispensable role in tolerance to peripheral antigens, but the origin of the Treg pool in the adult remains unclear. Thus, while thymic commitment of Treg has been demonstrated, evidence also exists for the peripheral recruitment of naive tissue-specific T cells into Treg functions. Anti-myelin basic protein TCR transgenic mice spontaneously develop autoimmune encephalomyelitis when 'monoclonal', but are protected by adoptive transfer of CD4+ cells from wild-type donors. We have now used this transfer system to investigate whether previously infused Treg can recruit transgenic T cells to regulatory functions. The results show that transgenic T cells from protected animals did not transfer tolerance to secondary recipients, and that elimination of donor Treg in protected recipients resulted in rapid onset of disease. In addition, Treg-containing T cell susbsets were highly enriched for proliferating cells in vivo, which was also the case for CD4+CD25+ T cells in normal animals. These observations thus exclude peripheral differentiation of Treg in this particular system, and indicate that expansion of thymically committed cells ensures the maintenance of the peripheral Treg pool in the adult