Using gene expression profiling, we show here that activation of B cells and professional antigen-presenting cells (APCs) induces the expression of common chemokines. Among these, CCL4 was the most potent chemoattractant of a CD4+CD25+ T cell population, which is a characteristic phenotype of regulatory T cells. Depletion of either regulatory T cells or CCL4 resulted in a deregulated humoral response, which culminated in the production of autoantibodies. This suggested that the recruitment of regulatory T cells to B cells and APCs by CCL4 plays a central role in the normal initiation of T cell and humoral responses, and failure to do this leads to autoimmune activation.

JUST IN front of the motor area of the cerebral cortex of man there is a supplementary representation of movements. This supplementary area is rather well circumscribed and is situated largely within the longitudinal interhemispheral fissure (Fig. 1). During the past several years we have seen a number of patients whose difficulties have necessitated surgical exploration and cortical stimulation within the longitudinal fissure. The findings cast new light upon the problem of cortical representation of motor and sensory function.This paper is an analysis of our observations on the properties of the superior and mesial intermediate precentral cortex in man. The results of local electrical stimulation and the patterns of focal seizures due to discharge in the area are presented, and an attempt is made to interpret the findings in terms of function. In addition, the results of an experimental approach to the analogous area in monkeys is reported. HISTORICAL NOTEThe function of the cortex which lies anterior to the motor area had elicited a great deal of interest, even before the demonstration by Campbell1 of the dis¬ tinctive anatomic properties of the intermediate precentrai area. Munk, cited by the Vogts,2 had foreshadowed Campbell's suggestion that in this region resided Jack¬ son's highest level of representation of movement. The experimental evidence, which was already considerable because of the work of

These data link minute amounts of aggregates with activation of the innate immune response, involving DC, resulting in T cell activation. Thus, when protein therapeutics with little or no clinical immunogenicity, such as trastuzumab, contain minute amounts of sub-visible aggregates, they are associated with significantly increased potential risk of clinical immunogenicity.

Regulatory T cells play an essential role in preventing fetal rejection by the maternal immune system. Here we show that, based on the expression of CCR5, regulatory T cells can be divided into a highly suppressive CCR5 ؉ and a far less suppressive CCR5 ؊ subpopulation, suggesting that the former represent the effector arm of regulatory T cells. Although regulatory T cells from CCR5 ؊/؊ gene deletion mutants still suppress, they are less effective mediators of maternal-fetal tolerance. The accumulation of CCR5 ؉ regulatory T cells at this site appears to be enhanced by alloantigen. This finding is in stark contrast to the systemic expansion of regulatory T cells during pregnancy, which appears to be alloantigenindependent. The fact that CCR5 ؉ regulatory T cells preferentially accumulate in the gravid uterus and that expression of CCR5 on regulatory T cells can be induced by activation lead us to propose that CCR5 is responsible for the accumulation of those regulatory T cells that have been activated by paternal antigens.effector T cells ͉ pregnancy ͉ tolerance ͉ chemokine receptor R egulatory T cells (T R cells) play an important role in the maintenance of peripheral tolerance and the prevention of autoimmunity (1). Where T R cells exert their suppressive function and what attracts them to and retains them at their site of action is poorly understood. Inducible T R cells (Tr1-like cells) have a preference for skin homing (2), whereas naturally occurring Foxp3 ϩ T R cells can be found in all lymphoid organs (3, 4). The CD103 ϩ subpopulation of T R cells has been shown to home to the site of inflammation (5); however, the mechanism by which this occurs remains elusive.Previously, we have demonstrated that naturally occurring T R cells mediate maternal tolerance to the fetus and can be found in the uterus during pregnancy (6). Although the uterine accumulation of macrophages (7), natural killer cells (8, 9), and eosinophils (10) has been extensively studied, there has been no insight on how T R cells find their way to the gravid uterus.Upon activation, professional antigen-presenting cells express the chemokine CCL4, which leads to the recruitment and/or retention of T R cells (11). Although it remains unclear which chemokine receptor is responsible for the CCL4-mediated effects on T R cells, biochemical studies have shown CCL4 to bind to the chemokine receptor CCR5 (12). Expression of CCR5 on T cells has been associated with both proinflammatory and antiinflammatory T cell function in mouse and human. CCR5 is thought to be expressed on antigen-experienced, effector T cells that home toward sites of inflammation outside the secondary lymphoid organs (13-15). CCR5 ϩ T cells have been shown to infiltrate inflamed sites such as the synovium of rheumatoid arthritis patients (16,17) and the central nervous system of mice with experimental autoimmune encephalomyelitis (18). Expression of CCR5 in pancreatic islets correlates with increased severity of diabetes in mice (19), and CCR5 is thought to mediate T cell migratio...