FoxP3 is a key transcription factor for the development and function of natural CD4(+) regulatory T cells (Treg cells). Here we show that human FoxP3(+)CD4(+) T cells were composed of three phenotypically and functionally distinct subpopulations: CD45RA(+)FoxP3(lo) resting Treg cells (rTreg cells) and CD45RA(-)FoxP3(hi) activated Treg cells (aTreg cells), both of which were suppressive in vitro, and cytokine-secreting CD45RA(-)FoxP3(lo) nonsuppressive T cells. The proportion of the three subpopulations differed between cord blood, aged individuals, and patients with immunological diseases. Terminally differentiated aTreg cells rapidly died whereas rTreg cells proliferated and converted into aTreg cells in vitro and in vivo. This was shown by the transfer of rTreg cells into NOD-scid-common gamma-chain-deficient mice and by TCR sequence-based T cell clonotype tracing in peripheral blood in a normal individual. Taken together, the dissection of FoxP3(+) cells into subsets enables one to analyze Treg cell differentiation dynamics and interactions in normal and disease states, and to control immune responses through manipulating particular FoxP3(+) subpopulations.

Citation Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T‐cell paradigm in pregnancy. Am J Reprod Immunol 2010T‐helper (Th) cells play a central role in modulating immune responses. The Th1/Th2 paradigm has now developed into the new Th1/Th2/Th17 paradigm. In addition to effector cells, Th cells are regulated by regulatory T (Treg) cells. Their capacity to produce cytokines is suppressed by immunoregulatory cytokines such as transforming growth factor (TGF)‐β and interleukin (IL)‐10 or by cell‐to‐cell interaction. Here, we will review the immunological environment in normal pregnancy and complicated pregnancy, such as implantation failure, abortion, preterm labor, and preeclampsia from the viewpoint of the new Th1/Th2/Th17 and Treg paradigms.

Repulsive guidance molecule (RGM) is a protein implicated in both axonal guidance and neural tube closure. We report RGMa as a potent inhibitor of axon regeneration in the adult central nervous system (CNS). RGMa inhibits mammalian CNS neurite outgrowth by a mechanism dependent on the activation of the RhoA–Rho kinase pathway. RGMa expression is observed in oligodendrocytes, myelinated fibers, and neurons of the adult rat spinal cord and is induced around the injury site after spinal cord injury. We developed an antibody to RGMa that efficiently blocks the effect of RGMa in vitro. Intrathecal administration of the antibody to rats with thoracic spinal cord hemisection results in significant axonal growth of the corticospinal tract and improves functional recovery. Thus, RGMa plays an important role in limiting axonal regeneration after CNS injury and the RGMa antibody offers a possible therapeutic agent in clinical conditions characterized by a failure of CNS regeneration.

Summary CD4+ CD25 bright regulatory T (Treg) cells have been identified as a principle regulator of tolerance during pregnancy. In the setting of pre-eclampsia, however, little is known about the dynamics of these cells. In the current study, we determined CD4 + CD25 bright Treg cells in the peripheral blood using flow cytometry and forkhead box P3 (FoxP3 + ) cells at the placental bed using immunohistochemical staining. Peripheral blood mononuclear cells (PBMC) of 38 pre-eclamptic cases (17 cases Japanese, 21 cases Polish), 40 normal late pregnancy subjects (20 subjects Japanese, 20 subjects Polish), and 21 non-pregnant healthy controls (10 subjects Japanese, 11 subjects Polish) were included. We found the percentage of CD25 bright cells within the CD4+ T cell population in PBMC was reduced significantly in both Japanese and Polish pre-eclamptic cases than in normal pregnancy subjects (P < 0·001) and non-pregnant healthy controls (P < 0·001). Also, the percentage of FoxP3+ cells within CD3 + T cells in the placental bed biopsy samples of pre-eclamptic cases were decreased compared to those in normal pregnancy subjects. These findings suggest that a decreased number of Treg cells was present in pre-eclampsia, and these changes might break the maternal tolerance to the fetus.

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The results suggest that endplate abnormalities are related to inflammation and axon growth induced by TNF. TNF expression and PGP 9.5-positive nerve in-growth in abnormal endplates may be a cause of low back pain.

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The precise and conceptual insight of circulating endothelial progenitor cell (EPC) kinetics is hampered by the absence of an assay system capable of evaluating the EPC differentiation cascade. An assay system for EPC colony formation was developed to delineate circulating EPC differentiation. EPC colony-forming assay using semisolid medium and single or bulk CD133؉ cells from umbilical cord blood exhibited the formation of two types of attaching cell colonies made of small or large cells featuring endothelial lineage potential and properties, termed small EPC colony-forming units and large EPC colony-forming units, respectively. In vitro and in vivo assays of each EPC colony-forming unit cell revealed a differentiation hierarchy from small EPC to large EPC colonies, indicating a primitive EPC stage with highly proliferative activity and a definitive EPC stage with vasculogenic properties, respectively. Experimental comparison with a conventional EPC culture assay system disclosed EPC colony-forming unit cells differentiate into noncolony-forming early EPC. The fate analysis of single CD133؉ cells into the endothelial and hematopoietic lineage was achieved by combining this assay system with a hematopoietic progenitor assay and demonstrated the development of colony-forming EPC and hematopoietic progenitor cells from a single hematopoietic stem cell. EPC colony-forming assay permits the determination of circulating EPC kinetics from single or bulk cells, based on the evaluation of hierarchical EPC colony formation. This assay further enables a proper exploration of possible links between the origin of EPC and hematopoietic stem cells, representing a novel and powerful tool to investigate the molecular signaling pathways involved in EPC biology. (Circ Res. 2011;109:20-37.) Key Words: clonogenic assay Ⅲ differentiation Ⅲ endothelial progenitor cell Ⅲ vasculogenesis D espite significant efforts in research and development with respect to endothelial progenitor cell (EPC) biology during the past 10 years after their initial isolation, 1 EPC remain a controversial topic among researchers because there is no definitive delineation of EPC, no clear differentiation hierarchy, or any unambiguously defined isolation protocol.EPC have been quantified and qualified either as cell populations identified by cell surface markers such as CD34, CD133, vascular endothelial growth factor receptor-2 (VEGFR-2), [1][2][3][4][5][6][7][8] or as adhesive cells 6,9,10 and colonies 11 using conventional EPC culture methods to produce spindle-shape adherent cells from peripheral blood (PB), bone marrow (BM), or umbilical cord blood (UCB) mononuclear cells (MNC) with endothelial growth factors and cytokines. These assays using conventional EPC culture protocols were simple and satisfactory to speculate on the vasculogenic properties of EPC-enriched fractions but have recently been criticized. These assays further group heterogeneous EPC into one qualitative category: "adhesive cultured EPC" without any hierarchical discrimination ...