IntroductionThere is now clear evidence that CD4 ϩ T cells contain a population of naturally immunosuppressive T cells characterized by constitutive expression of CD25, CTLA-4, and FOXP3. 1 Because not all potentially autoreactive T cells are deleted in the thymus, 2,3 peripheral control of T-cell responses by naturally occurring CD4 ϩ CD25 ϩ FOXP3 ϩ immunoregulatory T cells (T regs ) is crucial to prevent autoimmunity. 1 Depletion of T regs contributes to the induction of severe autoimmune diseases in animal models, and several studies have reported a defect of T regs in various human autoimmune diseases. 1,4,5 Despite extensive research to unravel the immunosuppressive function of T reg , the exact molecular mechanism of immunosuppression is still elusive. Promising targets for pharmacologic mimicking of T regs function remain undefined. Consequently, direct use of T regs for therapy is currently under examination. Therapeutic expansion or depletion of T regs with defined antigen specificity offers new treatment options for human diseases. 6 Because accumulation of T regs has been shown to be detrimental in cancer, 7 new insights into mechanisms of T reg homeostastis are required.To gain new insight into the modulation of T reg numbers as well as their antigen specificity, the development of natural T regs during ontogeny and in the adult needs to be explored. The peripheral T reg compartment consists mainly of thymus-derived T regs . 1 However, under specific circumstances T regs can also be generated out of conventional T cells (T convs ) (eg, if the antigen is targeted to immature dendritic cells [DCs]). [8][9][10] It has yet to be established how much "converted" T regs contribute to the total number of T regs in the periphery of adult mice and humans.At a given time, the overall number of T regs is defined by a balance of generation and demise of T regs . At the end of an immune reaction, T cells are depleted by apoptosis. Activation-induced cell death (AICD) through CD95/CD95L has been described as such an apoptosis-inducing mechanism. 11 While naive T cells are CD95 Ϫ and resistant to apoptosis induction, activated T cells (CD45RO hi ) up-regulate CD95 and become sensitive to apoptosis. Upon T-cell receptor (TCR) restimulation, activated effector T cells (T effs ) up-regulate CD95L and induce AICD through crosslinking of CD95 by CD95L. AICD eliminates T effs after an immune response and contributes to T-cell homeostasis. We have previously shown that most T regs constitutively express CD95 and can easily be killed via crosslinking of this death receptor by CD95L. 12 Together with the fact that most T regs express high levels of CD45RO, we contributed expertise in microarray analysis; J.P. contributed clinical samples; P.K. analyzed data and assisted in writing the paper; O.L. contributed clinical samples and assisted in writing the paper; and E.S.-P. designed research and wrote the paper.The online version of this article contains a data supplement. For personal use only. on April 5, 2019. by guest www....

Background: International guidelines suggest that growth of preterm infants should match intrauterine rates. However, the trajectory for extrauterine growth may deviate from the birth percentile due to an irreversible, physiological loss of extracellular fluid during postnatal adaptation to extrauterine conditions. To which "new" physiological growth trajectory preterm infants should adjust to after completed postnatal adaptation is unknown. This study analyzes the postnatal growth trajectories of healthy preterm infants using prospective criteria defining minimal support, as a model for physiological adaptation. Methods: International, multi-center, longitudinal, observational study at five neonatal intensive care units (NICUs). Daily weights until day of life (DoL) 21 of infants with undisturbed postnatal adaptation were analyzed (gestational ages: (i) 25-29 wk, (ii) 30-34 wk). results: 981 out of 3,703 admitted infants included. Maximum weight loss was 11% (i) and 7% (ii) by DoL 5, birth weight regained by DoL 15 (i) and 13 (ii). Infants transitioned to growth trajectories parallel to Fenton chart percentiles, 0.8 z-scores below their birth percentiles. The new trajectory after completed postnatal adaptation could be predicted for DoL 21 with R 2 = 0.96. conclusion: This study provides a robust estimate for physiological growth trajectories of infants after undisturbed postnatal adaptation. In the future, the concept of a target postnatal trajectory during NICU care may be useful. i mproved survival rates of very-low-birth-weight (<1,500 g birth weight) infants have shifted the focus of neonatal care onto improving postnatal growth and nutrition, aiming to achieve growth rates that optimize later health outcomes (1). Pediatric societies in North America and Europe have recommended that postnatal growth of preterm infants match the in utero growth rates of fetuses that remain in utero until full-term (2-4). These recommendations gain importance in light of the Developmental Origins of Health and Disease (DOHaD) hypothesis (5). The DOHaD concept suggests that suboptimal growth of a fetus or a newborn infant can impact the early onset of adult metabolic and cardiovascular diseases. In utero, the growth rate of an individual fetus is determined by its genetic potential and modified by "environmental" factors such as maternal nutrition, body composition, pathologies, or altitude above sea level. After birth, growth patterns of preterm infants are under external control by neonatal staff who modify the infants' nutrient intake. Figure 1 shows three hypothetical postnatal trajectories for a given preterm infant (27 wk of gestation, birth weight 1,000 g). It is of interest to note that these trajectories have similar slopes and hence not dramatically different growth rates. However, postnatal adjustment to different percentiles during the phase of stable growth will lead to different body compositions-potentially affecting later health outcomes.The current evidence for optimal postnatal growth trajectories is scarce....

Impaired suppressive capacity of CD4+CD25+FOXP3+ regulatory T cells (Treg) from peripheral blood of patients with multiple sclerosis (MS) has been reported by multiple laboratories. It is, however, currently unresolved whether Treg dysfunction in MS patients is limited to reduced control of peripheral T cell activation since most studies analyzed peripheral blood samples only. Here, we assessed early active MS lesions in brain biopsies obtained from 16 patients with MS by FOXP3 immunohistochemistry. In addition, we used six-color flow cytometry to determine numbers of Treg by analysis of FOXP3/CD127 expression in peripheral blood and cerebrospinal fluid (CSF) of 17 treatment-naïve MS patients as well as quantities of apoptosis sensitive CD45ROhiCD95hi cells in circulating and CSF Treg subsets. Absolute numbers of FOXP3+ and CD4+ cells were rather low in MS brain lesions and Treg were not detectable in 30% of MS biopsies despite the presence of CD4+ cell infiltrates. In contrast, Treg were detectable in all CSF samples and Treg with a CD45ROhiCD95hi phenotype previously shown to be highly apoptosis sensitive were found to be enriched in the CSF compared to peripheral blood of MS patients. We suggest a hypothetical model of intracerebral elimination of Treg by CD95L-mediated apoptosis within the MS lesion.