IntroductionNeutrophils are indispensable for host defense. 1 In addition, these cells play a detrimental role in the pathogenesis of many acute and chronic inflammatory diseases. They can cause tissue damage through aspecific activation of their repertoire of antimicrobial mechanisms. Neutrophils also inform and shape subsequent immunity 2 and can prolong inflammation by release of cytokines 3 and chemokines. 4 There is an emerging concept that neutrophils directly influence adaptive immune responses through pathogen shuttling to draining lymph nodes, 5,6 antigen presentation, 7 and modulation of T helper 1/T helper 2 responses. 8 Along this line, neutrophils have been reported to be an important component of myeloid-derived suppressor cells mediating lymphocyte suppression in various experimental models of acute 9 and chronic inflammation. 10 Targeting neutrophils in disease has mainly been focused on limiting their damaging capacity or directing their cytotoxic machinery to tumors. 11 Their immune modulatory functions have received little attention as potential targets in inflammatory diseases. This may at least in part be due to the current paradigm that these functions are of limited importance because of the generally accepted short circulatory half-life of neutrophils. Neutrophil lifespans have mainly been assessed by determination of ex vivo lifespans in culture (Ͻ 24 hours) and by transfer studies of ex vivo-manipulated neutrophils. The latter studies showed an estimated circulating half-life of approximately 8 hours in humans. 12 Ex vivo manipulation has been shown to have dramatic effects on neutrophil redistribution in vivo. 13 In mice, half-lives of 8 to 10 hours were reported when neutrophils were labeled in vivo. 14 In contrast, ex vivo labeling in mice showed that after transfer 90% of labeled neutrophils were cleared from the circulation within 4 hours, resulting in a half-life of less than 1.5 hours. 15 These differences between in vivo and ex vivo labeling strengthen our hypothesis that neutrophil transfer experiments may lead to an underestimation of neutrophil lifespan. The activation during ex vivo manipulation has probably led to retention in the lungs, 16 liver, spleen, and bone marrow (BM), 15 which may drastically reduce their circulatory half-life. To circumvent the complications introduced by ex vivo manipulation, we labeled the neutrophil pool in vivo in healthy mice and humans by administration of 2 H 2 O in drinking water. Acquisition of label and appearance of labeled neutrophils in the circulation is characterized by (1) the rate of division in the mitotic pool (MP) in the BM, (2) the transit time of newly formed neutrophils through the postmitotic pool (PMP) in the BM, and (3) the delay in mobilization of neutrophils from the PMP to the blood. With the use of a combination of gas chromatography and mass spectrometry the fraction of 2 H-labeled adenosine in the DNA of the proliferating neutrophil pool was measured, and the kinetics of the neutrophil pool was determined. Study des...

Parallels between T cell kinetics in mice and men have fueled the idea that a young mouse is a good model system for a young human, and an old mouse, for an elderly human. By combining in vivo kinetic labeling using deuterated water, thymectomy experiments, analysis of T cell receptor excision circles and CD31 expression, and mathematical modeling, we have quantified the contribution of thymus output and peripheral naive T cell division to the maintenance of T cells in mice and men. Aging affected naive T cell maintenance fundamentally differently in mice and men. Whereas the naive T cell pool in mice was almost exclusively sustained by thymus output throughout their lifetime, the maintenance of the adult human naive T cell pool occurred almost exclusively through peripheral T cell division. These findings put constraints on the extrapolation of insights into T cell dynamics from mouse to man and vice versa.

The genes encoding major histocompatibility (MHC) molecules are among the most polymorphic genes known for vertebrates. Since MHC molecules play an important role in the induction of immune responses, the evolution of MHC polymorphism is often explained in terms of increased protection of hosts against pathogens. Two selective pressures that are thought to be involved are (1) selection favoring MHC heterozygous hosts, and (2) selection for rare MHC alleles by host-pathogen coevolution. We have developed a computer simulation of coevolving hosts and pathogens to study the relative impact of these two mechanisms on the evolution of MHC polymorphism. We found that heterozygote advantage per se is insufficient to explain the high degree of polymorphism at the MHC, even in very large host populations. Host-pathogen coevolution, on the other hand, can easily account for realistic polymorphisms of more than 50 alleles per MHC locus. Since evolving pathogens mainly evade presentation by the most common MHC alleles in the host population, they provide a selective pressure for a large variety of rare MHC alleles. Provided that the host population is sufficiently large, a large set of MHC alleles can persist over many host generations under hostpathogen coevolution, despite the fact that allele frequencies continuously change.

Neutrophils are the most abundant white blood cells and are indispensable for host defense. Recently, they have also been implicated in immune regulation and suppression. The latter functions seem hard to reconcile with the widely held view that neutrophils are very short-lived, with a circulatory half-life of <7 h. To reopen the discussion on the average neutrophil half-life, we review and discuss experiments performed in the 1950s, 1960s, and 1970s, as well as recent in vivo labeling experiments. We reappraise the current knowledge on neutrophil half-lives, including their production in the bone marrow, their residency in the circulation and marginated pool, and their exit from the circulation.

Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation.

The parameter domain for which the quasi-steady state assumption is valid can be considerably extended merely by a simple change of variable. This is demonstrated for a variety of biologically significant examples taken from enzyme kinetics, immunology and ecology.

Key Points• Life span estimates can be sensitive to the duration of stable isotope label administration, explaining discrepancies in the literature.• Multiexponential models are needed to obtain reliable leukocyte life span estimates.Quantitative knowledge of the turnover of different leukocyte populations is a key to our understanding of immune function in health and disease. Much progress has been made thanks to the introduction of stable isotope labeling, the state-of-the-art technique for in vivo quantification of cellular life spans. Yet, even leukocyte life span estimates on the basis of stable isotope labeling can vary up to 10-fold among laboratories. We investigated whether these differences could be the result of variances in the length of the labeling period among studies. To this end, we performed deuterated water-labeling experiments in mice, in which only the length of label administration was varied. The resulting life span estimates were indeed dependent on the length of the labeling period when the data were analyzed using a commonly used single-exponential model. We show that multiexponential models provide the necessary tool to obtain life span estimates that are independent of the length of the labeling period. Use of a multiexponential model enabled us to reduce the gap between human T-cell life span estimates from 2 previously published labeling studies. This provides an important step toward unambiguous understanding of leukocyte turnover in health and disease. (Blood. 2013;122(13):2205-2212

No abstract