In mice, recent thymic emigrants (RTEs) make up a large part of the naïve T cell pool and have been suggested to be a distinct short-lived pool. In humans, however, the life span and number of RTEs are unknown. Although 2 H2O labeling in young mice showed high thymic-dependent daily naïve T cell production, long term upand down-labeling with 2 H2O in human adults revealed a low daily production of naïve T cells. Using mathematical modeling, we estimated human naïve CD4 and CD8 T cell half-lives of 4.2 and 6.5 years, respectively, whereas memory CD4 and CD8 T cells had half-lives of 0.4 and 0.7 year. The estimated half-life of recently produced naïve T cells was much longer than these average half-lives. Thus, our data are incompatible with a substantial short-lived RTE population in human adults and suggest that the few naïve T cells that are newly produced are preferentially incorporated in the peripheral pool. recent thymic emigrants ͉ T cell half-lives ͉ T cell production T he role of the thymus in HIV infection is still poorly understood (1, 2). On the one hand, thymic failure has been suggested to play a crucial role in CD4 T cell loss during HIV infection (3), and rapid thymic rebound has been proposed to be responsible for T cell reconstitution during anti-viral treatment (4). However, it has been argued that thymic output in adults might be too low to have a large impact on CD4 T cell depletion (5). In general, these issues are addressed with estimates of thymic output, naïve and memory T cell production rates, and life spans that are simply extrapolated from observations in mice, monkeys, and lymphopenic or irradiated humans (6-11).Naïve T cells are generally thought to turnover relatively slowly, but it has been suggested that, in mice, a considerable part of the naïve T cell pool consists of RTEs with relatively rapid turnover (9, 10, 12). In humans, naïve T cell numbers, T cell receptor excision circles (TRECs), and expression of CD31 have been used to measure thymic output (7,13,14). Dion et al. (4) observed rapid changes in the Sj/V␤ TREC ratio within 3 months after infection with HIV, which suggested the presence of a rapidly turning over RTE pool in human adults containing most of the TRECs in the periphery, similar to young rodents and chickens (15, 16). However, because TRECs are long-lived, none of these approaches is specific for T cells that have recently emigrated from the thymus (1, 2, 5), and, therefore, they fail to quantify thymic output in humans.Peripheral T cell proliferation might also contribute to the maintenance of the naïve T cell pool in human adults; however, it is unclear which fraction of these cells remains in the naïve T cell pool (17). The contribution of RTEs and peripheral T cell proliferation to the maintenance of the naïve T cell pool can only be determined by studying the fate of newly produced T cells. In vivo labeling with stable isotopes in combination with appropriate mathematical analysis of these data provides a way to obtain T cell decay and production rates ...

Tumor necrosis factor has been implicated in the activation of blood coagulation in septicemia, a condition commonly associated with intravascular coagulation and disturbances of hemostasis. To evaluate the early dynamics and the route of the in vivo coagulative response to tumor necrosis factor, we performed a controlled study in six healthy men, monitoring the activation of the common and intrinsic pathways of coagulation with highly sensitive and specific radioimmunoassays. Recombinant human tumor necrosis factor, administered as an intravenous bolus injection (50 micrograms per square meter of body-surface area), induced an early and short-lived rise in circulating levels of the activation peptide of factor X, reaching maximal values after 30 to 45 minutes (mean +/- SEM increase after 45 minutes, 34.2 +/- 18.2 percent; tumor necrosis factor vs. saline, P = 0.015). This was followed by a gradual and prolonged increase in the plasma concentration of the prothrombin fragment F1+2, peaking after four to five hours (mean increase after five hours, 348.0 +/- 144.8 percent; tumor necrosis factor vs. saline, P less than 0.0001). These findings signify the formation of factor Xa (activated factor X) and the activation of prothrombin. Activation of the intrinsic pathway could not be detected by a series of measurements of the plasma levels of factor XII, prekallikrein, factor XIIa-C1 inhibitor complexes, kallikrein-C1 inhibitor complexes, and the activation peptide of factor IX. The delay between the maximal activation of factor X and that of prothrombin amounted to several hours, indicating that neutralization of factor Xa activity was slow. We conclude that a single injection of tumor necrosis factor elicits a rapid and sustained activation of the common pathway of coagulation, probably induced through the extrinsic route. Our results suggest that tumor necrosis factor could play an important part in the early activation of the hemostatic mechanism in septicemia.

Type 2 diabetes is associated with altered immune and hemostatic responses. We investigated the selective effects of hyperglycemia and hyperinsulinemia on innate immune, coagulation, and fibrinolytic responses during systemic inflammation. Twenty-four healthy humans were studied for 8 hours during clamp experiments in which either plasma glucose, insulin, both, or none was increased, depending on randomization. Target plasma concentrations were 5 versus 12 mM for glucose, and 100 versus 400 pmol/L for insulin. After 3 hours, 4 ng/kg Escherichia coli endotoxin was injected intravenously to induce a systemic inflammatory and procoagulant response. Endotoxin administration induced cytokine release, activation of neutrophils, endothelium and coagulation, and inhibition of fibrinolysis. Hyperglycemia reduced neutrophil degranulation (plasma elastase levels, P < .001) and exaggerated coagulation (plasma concentrations of thrombin-antithrombin complexes and soluble tissue factor, both P < .001). Hyperinsulinemia attenuated fibrinolytic activity due to elevated plasminogen activatorinhibitor-1 levels (P < .001). Endothelial cell activation markers and cytokine concentrations did not differ between clamps. We conclude that in humans with systemic inflammation induced by intravenous endotoxin administration hyperglycemia impairs neutrophil degranulation and potentiates coagulation, whereas hyperinsulinemia inhibits fibrinolysis. These data suggest that type 2 diabetes patients may be especially vulnerable to prothrombotic events during inflammatory states. IntroductionType 2 diabetes is associated with an increased risk for thrombotic complications. 1 It has been estimated that 80% of diabetic patients die from acute arterial thrombosis, such as myocardial infarction and ischemic cerebrovascular events. 2 Apart from the accelerated development of atherosclerosis in patients with diabetes, these patients were also found to have an increased risk of thrombotic events, explained by an increased procoagulant activity combined with a decreased fibrinolytic capacity. 1 In addition, diabetic patients are prone to develop infectious diseases and more frequently die from infections than nondiabetic controls. 3 The enhanced infection risk is, at least in part, related to an impaired innate immune system. Concentrations of cytokines, molecules that orchestrate the innate immune response, are altered in diabetic patients, 4,5 and several functions of neutrophils, specialized in the killing of invading bacteria, are suppressed. 6 A prominent feature of type 2 diabetes is the concurrent existence of hyperglycemia and hyperinsulinemia. We recently demonstrated that hyperglycemia and hyperinsulinemia have differential and selective effects on the hemostatic balance in healthy humans. 7 In a strictly controlled setting, we showed that acute hyperglycemia activates coagulation independent of insulin levels, whereas hyperinsulinemia inhibits fibrinolysis irrespective of plasma glucose levels. 7 Inflammation and coagulation are tightly inte...