To determine site and mechanism of suppression, regulatory T cell (Treg) migration and function were investigated in an islet allograft model. Treg first migrated from blood to the inflammed allografts, this depended on CCR2, CCR4, CCR5, and P- and E-selectin ligands, and was essential for suppression of alloimmunity. In the allograft, Treg were activated, upregulated effector molecules, migrated to the draining lymph nodes (dLN) in a CCR2, CCR5, and CCR7 fashion, and this movement was essential for optimal suppression. Treg inhibited dendritic cell migration in a TGFβ and IL-10 dependent fashion; and suppressed antigen specific T effector cell migration, accumulation, and proliferation in dLNs and allografts. These results showed that sequential migration from blood to the target tissue and then to dLNs were required for nTreg to differentiate and execute fully their suppressive function, by inhibiting DC in the peripheral tissue, and T effector cell responses in dLN and allografts.

Glut-1 deficiency syndrome (Glut-1 DS, OMIM #606777) is characterized by infantile seizures, developmental delay, acquired microcephaly and hypoglycorrhachia. It is caused by haploinsufficiency of the blood-brain barrier hexose carrier. Heterozygous mutations or hemizygosity of the GLUT-1 gene cause Glut-1 DS. We generated a heterozygous haploinsufficient mouse model by targeted disruption of the promoter and exon 1 regions of the mouse GLUT-1 gene. GLUT-1+/- mice have epileptiform discharges on electroencephalography (EEG), impaired motor activity, incoordination, hypoglycorrhachia, microencephaly, decreased brain glucose uptake as measured by positron emission tomography (PET) scan and decreased brain Glut-1 expression by western blot (66%). The GLUT-1+/- murine phenotype mimics the classical human presentation of Glut-1 DS. This GLUT-1+/- mouse model creates an opportunity to investigate Glut-1 function, to examine the pathophysiology of Glut-1 DS in vivo and to evaluate new treatment strategies.

High levels of ventricular lactate, the brain spectroscopic signature of MELAS, are associated with more severe neurologic impairment.

CD4 + CD25 + regulatory T cells (Treg) are potent suppressors, and play important roles in autoimmunity and transplantation. Recent reports suggest that CD4 + CD25 + Treg are not a homogeneous cell population, but the differences in phenotype, function, and mechanisms among different subsets are unknown. Here, we demonstrate CD4 + CD25 + Treg cells can be divided into subsets according to cell-surface expression of CD62L. While both subsets express foxp3 and are anergic, the CD62L + population is more potent on a per cell basis, and proliferates and maintains suppressive function far better than the CD62L-population and unseparated CD4 + CD25 + Treg. The CD62L + population preferentially migrates to CCL19, MCP-1 and FTY720. Both CD62L + and CD62L-subsets prevent the development of autoimmune gastritis and colitis induced by CD4 + CD25-CD45RB high cells in severe combined immunodeficiency (SCID) mice. Overall, these results suggest CD4 + CD25 + Treg are not a homogenous cell population, but can be divided into at least two subsets according to CD62L expression. The CD62L + subset is a more potent suppressor than the CD62L-population or unfractionated CD4 + CD25 + Treg cells, can be expanded far more easily in culture, and is more responsive to chemokine-driven migration to secondary lymphoid organs. These properties may have significant implications for the clinical manipulation of the CD4 + CD25 + CD62L + cells. Tolerance is a feature of the immune system that is intimately related to discrimination between self and nonself. Clonal deletion of self-reactive T cells in the thymus is a primary tolerance mechanism, while induction of unresponsiveness or anergy in post thymic T cells may be required for the establishment of peripheral tolerance. Recent data show that Treg may play a critical role in the induction and maintenance of immune tolerance (1-5). Various types of Treg cells have been described, including Tr1 cells, Th3 cells, CD4 + CD25 + Treg cells, and others (6). CD4 + CD25 + Treg cells were first described by Sakaguchi (7). Five to 10% of CD4 + T cells constitutively expressed the a chain of IL-2-receptor (CD25) and were crucial for the control of autoreactive T cells in vivo. These cells are generated in the thymus of naïve mice, perhaps via altered negative selection by self-antigen (8). Subsequent in vitro studies showed that CD4 + CD25 + cells are typically anergic, unresponsive to TCR stimulation alone, but proliferate after addition of exogenous IL-2 (9). These cells suppress the proliferation of other CD4 + and CD8+ T cells in an antigen-nonspecific manner via a cell contact-dependent, cytokine-independent mechanism (10,11). A similar population of CD4 + CD25 + Treg cells has been defined in humans, with identical phenotypic and functional properties (12-15).CD4 + CD25 + Treg are potent suppressors in a number of in vivo models of autoimmunity, including gastritis, thyroiditis, inflammatory bowel disease and insulin-dependent diabetes (16)(17)(18)(19). Regulation of disease activity in vivo seems...