The expansion of modern human populations in Africa 80,000 to 60,000 years ago and their initial exodus out of Africa have been tentatively linked to two phases of technological and behavioral innovation within the Middle Stone Age of southern Africa—the Still Bay and Howieson's Poort industries—that are associated with early evidence for symbols and personal ornaments. Establishing the correct sequence of events, however, has been hampered by inadequate chronologies. We report ages for nine sites from varied climatic and ecological zones across southern Africa that show that both industries were short-lived (5000 years or less), separated by about 7000 years, and coeval with genetic estimates of population expansion and exit times. Comparison with climatic records shows that these bursts of innovative behavior cannot be explained by environmental factors alone.

IntroductionDendritic cells (DCs) have long been known to be the most important antigen-presenting cell for priming T-helper cells. 1 It is now also clear that DCs are involved in establishing tolerance to self antigens and nonpathogenic foreign antigens. DCs located in the periphery internalize both self and nonself antigens and migrate to lymph nodes. 2,3 Depending on their state of maturation, the stimulatory signals they have received, and the antigens they are presenting, DCs can activate the lymphocytes to respond to the antigen, or to induce tolerance to the presented antigen. 1 The ability of DCs to induce immunity or tolerance is a consequence of a number of factors. These include the expression of costimulatory molecules on their surface (such as CD40, CD80, and 86) and the secretion of cytokines. 3,4 In recent years the importance of the expression of the indoleamine 2, 3-dioxygenase enzyme (IDO) by DCs has been recognized. 5 This enzyme catabolizes tryptophan, which is essential for lymphocyte function, and has an important role in immunomodulation in sites such as the placenta, where it prevents T-cell-mediated rejection of allogeneic fetuses. 6 DCs that express high levels of IDO cannot activate T-cell responses, and so are capable of inducing tolerance to antigens that they express. Interferon ␥ (IFN-␥) is a powerful inducer of IDO activity in DCs. Recently, it has been shown that cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) 7 and surface bound CTLA4 8 act to up-regulate IDO expression in DCs, possibly by increasing IFN-␥ production.This ability of DCs to induce either tolerance or immunity offers considerable opportunities for their use in therapy. Thus activated DCs (referred to as mature DCs [mDCs]) can be used to induce immunity to pathogens or tumor-related antigens, while immature DCs (iDCs), which are tolerogenic, may have a role in controlling autoimmune disease or transplantation. Such strategies may also involve the genetic modification of DCs, either to express an antigen of interest or to modulate the function of the cells.At present the most efficient method for genetic modification of DCs is to use viral vectors, though there are a number of nonviral strategies that are being developed. In particular, adenoviral (Ad) or lentiviral vectors have all been shown to be effective in transducing DCs. However, the transduction of DCs by these vectors may be associated with alterations in the phenotype and function of the cells.Viruses can activate iDCs to become mDCs by a number of pathways, 9-12 in particular through the presence of double-stranded For personal use only. on May 10, 2018. by guest www.bloodjournal.org From (ds) RNA in virally infected cells. Perhaps the best-characterized pathways are the coupled 2-5A synthetase/RNase L and the protein kinase R (PKR) pathways. 13 The 2-5A synthetase/RNase L system is composed of the 2Ј-5Ј oligoadenylate synthetase (OAS) family of dsRNA-dependent enzymes and dormant, cytosolic RNAase L. dsRNA-activated 2Ј-5Ј OAS synth...

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Summary Uncommitted (naive) CD4+ T helper cells (Thp) can be induced to differentiate to specific lineages according to the local cytokine milieu, towards T helper type 1 (Th1), Th2, Th17 and regulatory T cell (Treg) phenotypes in a mutually exclusive manner. Each phenotype is characterized by unique signalling pathways and expression of specific transcription factors, notably T-bet for Th1, GATA-3 for Th2, forkhead box P3 ( Unexpectedly, however, a number of groups have now described conversion of Tregs to the Th17 phenotype induced by appropriate inflammatory stimuli. These observations are particularly relevant in the context of cell therapy but may also explain some of the dysregulation seen in autoimmune diseases. In this paper, we review Treg to Th17 conversion and propose some potential mechanisms for this phenomenon.

Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are “plastic”, and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1β, but not IL-6. “IL-17 potential” is restricted to population III (CD4+CD25hiCD127loCD45RA−) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161+ population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.

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CD4+ CD25+ regulatory T cells (Tregs) have far-reaching immunotherapeutic applications, the realization of which will require a greater understanding of the factors influencing their function and phenotype during ex vivo manipulation. In murine models, IL-2 plays an important role in both the maintenance of a functional Treg population in vivo and the activation of suppression in vitro. We have found that IL-2 maintains optimal function of human CD4+ CD25+ Tregs in vitro and increases expression of both forkhead box protein 3, human nomenclature (FOXP3) and the distinctive markers CD25, cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor superfamily member number 18 (GITR). Although IL-2 reduced spontaneous apoptosis of Tregs, this property alone could not account for the optimal maintenance of the regulatory phenotype. The inhibition of phosphatidylinositol 3-kinase (PI3K) signaling by LY294002, a chemical inhibitor of PI3K, abolished the maintenance of maximal suppressive potency by IL-2, yet had no effect on the up-regulation of FOXP3, CD25, CTLA-4 and GITR. Other common gamma chain (gammac) cytokines-IL-4, IL-7 and IL-15-had similar properties, although IL-4 showed a unique lack of effect on the expression of FOXP3 or Treg markers despite maintaining maximal regulatory function. Taken together, our data suggest a model in which the gammac cytokines IL-2, IL-4, IL-7 and IL-15 maintain the optimal regulatory function of human CD4+ CD25+ T cells in a PI3K-dependent manner, offering new insight into the effective manipulation of Tregs ex vivo.

SummaryBackground and objectives Cell-based therapy with natural (CD4 + CD25 hi CD127 lo ) regulatory T cells to induce transplant tolerance is now technically feasible. However, regulatory T cells from hemodialysis patients awaiting transplantation may be functionally/numerically defective. Human regulatory T cells are also heterogeneous, and some are able to convert to proinflammatory Th17 cells. This study addresses the suitability of regulatory T cells from hemodialysis patients for cell-based therapy in preparation for the first clinical trials in renal transplant recipients (the ONE Study).Design, setting, participants, & measurements Healthy controls and age-and sex-matched hemodialysis patients without recent illness/autoimmune disease on established, complication-free hemodialysis for a minimum of 6 months were recruited. Circulating regulatory T cells were studied by flow cytometry to compare the regulatory T cell subpopulations. Regulatory T cells from members of each group were compared for suppressive function and plasticity (IL-17-producing capacity) before and after in vitro expansion with and without Rapamycin, using standard assays.Results Both groups had similar total regulatory T cells and subpopulations I and III. In each subpopulation, regulatory T cells expressed similar levels of the function-associated markers CD27, CD39, HLA-DR, and FOXP3. Hemodialysis regulatory T cells were less suppressive, expanded poorly compared with healthy control regulatory T cells, and produced IL-17 in the absence of Rapamycin. However, Rapamycin efficiently expanded hemodialysis regulatory T cells to a functional and stable cell product.Conclusions Rapamycin-based expansion protocols should enable clinical trials of cell-based immunotherapy for the induction of tolerance to renal allografts using hemodialysis regulatory T cells.