Immune response dynamics in coronavirus disease 2019 and their severe manifestations have largely been studied in circulation. Here, we examined the relationship between immune processes in the respiratory tract and circulation through longitudinal phenotypic, transcriptomic, and cytokine profiling of paired airway and blood samples from patients with severe COVID-19 relative to heathy controls. In COVID-19 airways, T cells exhibited activated, tissue-resident, and protective profiles; higher T cell frequencies correlated with survival and younger age. Myeloid cells in COVID-19 airways featured hyperinflammatory signatures, and higher frequencies of these cells correlated with mortality and older age. In COVID-19 blood, aberrant CD163 + monocytes predominated over conventional monocytes, and were found in corresponding airway samples and in damaged alveoli. High levels of myeloid chemoattractants in airways suggest recruitment of these cells through a CCL2-CCR2 chemokine axis. Our findings provide insights into immune processes driving COVID-19 lung pathology with therapeutic implications for targeting inflammation in the respiratory tract.

Why do parasites harm their hosts? Conventional wisdom holds that because parasites depend on their hosts for survival and transmission, they should evolve to become benign, yet many parasites cause harm. Theory predicts that parasites could evolve virulence (i.e., parasite-induced reductions in host fitness) by balancing the transmission benefits of parasite replication with the costs of host death. This idea has led researchers to predict how human interventions-such as vaccines-may alter virulence evolution, yet empirical support is critically lacking. We studied a protozoan parasite of monarch butterflies and found that higher levels of within-host replication resulted in both higher virulence and greater transmission, thus lending support to the idea that selection for parasite transmission can favor parasite genotypes that cause substantial harm. Parasite fitness was maximized at an intermediate level of parasite replication, beyond which the cost of increased host mortality outweighed the benefit of increased transmission. A separate experiment confirmed genetic relationships between parasite replication and virulence, and showed that parasite genotypes from two monarch populations caused different virulence. These results show that selection on parasite transmission can explain why parasites harm their hosts, and suggest that constraints imposed by host ecology can lead to population divergence in parasite virulence.coevolution ͉ Danaus plexippus ͉ disease ͉ epidemiology ͉ pathogen P arasites are arguably the most common life form on earth (1), and understanding their evolution has increasing relevance for predicting their effects on human, agricultural, and wild populations (2-8). By definition, parasites cause harm to their hosts (i.e., they cause virulence), but explaining why they do so remains a challenge for evolutionary biologists. A fundamental question is why parasites that depend on hosts for their own survival and transmission cause disease or even kill their hosts. The most popular evolutionary explanation asserts that virulence is an unavoidable consequence of selection to maximize parasite fitness (9-17). Parasites must replicate within hosts to produce transmission stages, but this also consumes host resources, damages host tissues, and provokes immune clearance, thereby shortening the infectious period over which transmission can take place. Parasites thus face a trade-off between the benefits of increased replication (i.e., increased transmission rate) and the costs (i.e., virulence or immune clearance), resulting in highest fitness at intermediate levels of parasite replication.This ''trade-off hypothesis'' underlies many theoretical studies and is advocated to inform public health decisions (6,7,13,18), yet there remains a serious lack of empirical evidence (19,20). A small number of studies have shown positive relationships between within-host replication and virulence (21) and between virulence and parasite transmission potential (22-24), or have shown optimal transmission at an inte...

Memory CD8 T cells, generated by natural pathogen exposure or intentional vaccination, protect the host against specific viral infections. It has long been proposed that the number of memory CD8 T cells in the host is inflexible, and that individual cells are constantly competing for limited space. Consequently, vaccines that introduce over-abundant quantities of memory CD8 T cells specific for an agent of interest could have catastrophic consequences for the host by displacing memory CD8 T cells specific for all previous infections. To test this paradigm, we developed a vaccination regimen in mice that introduced as many new long-lived memory CD8 T cells specific for a single vaccine antigen as there were memory CD8 T cells in the host before vaccination. Here we show that, in contrast to expectations, the size of the memory CD8 T-cell compartment doubled to accommodate these new cells, a change due solely to the addition of effector memory CD8 T cells. This increase did not affect the number of CD4 T cells, B cells or naive CD8 T cells, and pre-existing memory CD8 T cells specific for a previously encountered infection were largely preserved. Thus, the number of effector memory CD8 T cells in the mammalian host adapts according to immunological experience. Developing vaccines that abundantly introduce new memory CD8 T cells should not necessarily ablate pre-existing immunity to other infections.

What are the rules that govern a naive T cell's prospects for survival or division after export from the thymus into the periphery? To help address these questions, we combine data from existing studies with robust mathematical models to estimate the absolute contributions of thymopoiesis, peripheral division, and loss or differentiation to the human naive CD4 ؉ T-cell pool between the ages of 0 and 20 years. Despite their decline in frequency in the blood, total body numbers of naive CD4 ؉ T cells increase throughout childhood and early adulthood. Our analysis shows that postthymic proliferation contributes more than double the number of cells entering the pool each day from the thymus. This ratio is preserved with age; as the thymus involutes, the average time between naive T-cell divisions in the periphery lengthens. We also show that the expected residence IntroductionAn adult human has a population of approximately 10 11 naive T cells circulating in the peripheral lymphoid organs and blood. From early in development, this population is generated and sustained by thymic export and division on the periphery, and is estimated to comprise at least 10 8 different T-cell receptor specificities, 1 providing a broad spectrum of protection in a diverse pathogen environment.The rate of export of naive T cells from the thymus declines substantially with age in healthy persons, 2 but estimates of the total number of cells exported from the thymus over a person's lifetime are still approximately 10-fold greater than the total number of naive T cells in an adult at any one time; an estimate of daily thymic output based on the study of Steinmann et al 2 integrated over 80 years is 5 ϫ 10 12 cells. Furthermore, at least a subset of naive cells continues to divide slowly after release from the thymus into the periphery. These 2 observations imply that turnover and replacement occurs in the naive T-cell pool. What are the rules that govern a circulating naive cell's prospects for survival and proliferation? Do these rules change as we age and, if so, how? Identifying these rules requires a combination of experimental approaches and mathematical models, and will provide an essential background for understanding the dynamics of the T-cell pool when it is dysregulated-for example, during the reconstitution of the T-cell pools after medical interventions that induce lymphopenia, or after antiretroviral therapy in HIV infection. 3 As a step toward answering these questions, here we quantify the contributions of proliferation, loss, and thymic input to the development of the healthy naive T-cell compartment. We focus on naive CD4 ϩ T-cell dynamics in persons up to age 20. The youngest age groups might be expected to have the most dynamic T-cell populations because rates of thymic export are highest and physiologic growth, in particular growth of blood volume and lymphoid tissue, is continuously altering the environment in which the T cells circulate and encounter homeostatic signals.Currently, the most direct methods for measurin...

It has long been recognized that the T-cell compartment has more CD4 helper than CD8 cytotoxic T cells, and this is most evident looking at T-cell development in the thymus. However, it remains unknown how thymocyte development so favors CD4 lineage development. To identify the basis of this asymmetry, we analyzed development of synchronized cohorts of thymocytes in vivo and estimated rates of thymocyte death and differentiation throughout development, inferring lineage-specific efficiencies of selection. Our analysis suggested that roughly equal numbers of cells of each lineage enter selection and found that, overall, a remarkable ∼75% of cells that start selection fail to complete the process. Importantly it revealed that class I-restricted thymocytes are specifically susceptible to apoptosis at the earliest stage of selection. The importance of differential apoptosis was confirmed by placing thymocytes under apoptotic stress, resulting in preferential death of class I-restricted thymocytes. Thus, asymmetric death during selection is the key determinant of the CD4:CD8 ratio in which T cells are generated by thymopoiesis. CD4 T cells | CD8 T cellsD evelopment of CD4 and CD8 lineage cells from common thymic precursors is one of the most fundamental developmental processes in the adaptive immune system. The predominance of CD4 over CD8 T-cell populations in the periphery has been apparent since helper and cytotoxic T cells were first delineated more than 30 y ago (1), but the cause of this signature bias has remained obscure. A key contribution arises from the ratio in which CD4 and CD8 lineage T cells are generated by the thymus. Single-positive (SP) thymocytes exist in the thymus at ∼4:1, a ratio that is highly conserved across mouse strains and other species, suggesting that the developmental mechanisms involved are fundamental to the processes that give rise to mature T cells in the thymus. During thymocyte development, T-cell antigen receptor (TCR) genes undergo somatic rearrangements to generate a broad repertoire of TCR structures. Negative and positive selection of thymocytes results in the deletion of autoreactive thymocytes and ensures that class I and class II MHC reactivity is correlated with CD8 and CD4 lineage specification. The molecular mechanisms underpinning these processes are increasingly well understood. Although survival of thymocytes is regulated by expression of Bcl2 family members, up-regulation of the BH3-only family member Bim has been specifically implicated as a key event in negative selection of thymocytes (2). During positive selection, class II recognition is thought to induce strong persistent signaling that results in a cascade of transcriptional regulation by factors such as GATA3 and T-helper-inducing POZ/Krüppel-like factor, which results in fixation of cells to the CD4 lineage (3, 4). In contrast, weaker or transient signaling by class I MHC results in the cytokine-dependent induction of a Runx3-mediated transcriptional program that induces CD8 lineage commitment (5-8).Despit...