Theories and quantification of thymic selection

The peripheral T cell repertoire is sculpted from prototypic T cells in the thymus bearing randomly generated T cell receptors (TCR) and by a series of developmental and selection steps that remove cells that are unresponsive or overly reactive to self-peptide–MHC complexes. The challenge of understanding how the kinetics of T cell development and the statistics of the selection processes combine to provide a diverse but self-tolerant T cell repertoire has invited quantitative modeling approaches, which are reviewed here

Asymmetric thymocyte death underlies the CD4:CD8 T-cell ratio in the adaptive immune system

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

Models of self-peptide sampling by developing T cells identify candidate mechanisms of thymic selection

Conventional and regulatory T cells develop in the thymus where they are exposed to samples of self-peptide MHC (pMHC) ligands. This probabilistic process selects for cells within a range of responsiveness that allows the detection of foreign antigen without excessive responses to self. Regulatory T cells are thought to lie at the higher end of the spectrum of acceptable self-reactivity and play a crucial role in the control of autoimmunity and tolerance to innocuous antigens. While many studies have elucidated key elements influencing lineage commitment, we still lack a full understanding of how thymocytes integrate signals obtained by sampling self-peptides to make fate decisions. To address this problem, we apply stochastic models of signal integration by T cells to data from a study quantifying the development of the two lineages using controllable levels of agonist peptide in the thymus. We find two models are able to explain the observations; one in which T cells continually re-assess fate decisions on the basis of multiple summed proximal signals from TCR-pMHC interactions; and another in which TCR sensitivity is modulated over time, such that contact with the same pMHC ligand may lead to divergent outcomes at different stages of development. Neither model requires that T and T are differentially susceptible to deletion or that the two lineages need qualitatively different signals for development, as have been proposed. We find additional support for the variable-sensitivity model, which is able to explain apparently paradoxical observations regarding the effect of partial and strong agonists on T and T development

On the control of acute rodent malaria infections by innate immunity

Does specific immunity, innate immunity or resource (red blood cell) limitation control the first peak of the blood-stage parasite in acute rodent malaria infections? Since mice deficient in specific immunity exhibit similar initial dynamics as wild-type mice it is generally viewed that the initial control of parasite is due to either limitation of resources (RBC) or innate immune responses. There are conflicting views on the roles of these two mechanisms as there is experimental evidence supporting both these hypotheses. While mathematical models based on RBC limitation are capable of describing the dynamics of primary infections, it was not clear whether a model incorporating the key features of innate immunity would be able to do the same. We examine the conditions under which a model incorporating parasite and innate immunity can describe data from acute <i>Plasmodium chabaudi</i> infections in mice. We find that innate immune response must decay slowly if the parasite density is to fall rather than equilibrate. Further, we show that within this framework the differences in the dynamics of two parasite strains are best ascribed to differences in susceptibility to innate immunity, rather than differences in the strains' growth rates or their propensity to elicit innate immunity. We suggest that further work is required to determine if innate immunity or resource limitation control acute malaria infections in mice

Optimal Trading Ratios for Pollution Permit Markets ∗

We analyze a novel method for improving the efficiency of pollution permit markets by optimizing the way in which emissions are exchanged through trade. Under fullinformation, it is optimal for emissions to exchange according to the ratio of marginal damages. However, under a canonical model with asymmetric information between the regulator and the sources of pollution, we show that these marginal damage trading ratios are generally not optimal, and we show how to modify them to improve efficiency. We calculate the optimal trading ratios for a global carbon market and for a regional nitrogen market. In these examples, the gains from using optimal trading ratios rather than marginal damage trading ratios range from substantial to trivial, which suggests the need for careful consideration of the structure of asymmetric information when designing permit markets

Compensation Following Bilateral Vestibular Damage

Bilateral loss of vestibular inputs affects far fewer patients than unilateral inner ear damage, and thus has been understudied. In both animal subjects and human patients, bilateral vestibular hypofunction (BVH) produces a variety of clinical problems, including impaired balance control, inability to maintain stable blood pressure during postural changes, difficulty in visual targeting of images, and disturbances in spatial memory and navigational performance. Experiments in animals have shown that non-labyrinthine inputs to the vestibular nuclei are rapidly amplified following the onset of BVH, which may explain the recovery of postural stability and orthostatic tolerance that occurs within 10 days. However, the loss of the vestibulo-ocular reflex and degraded spatial cognition appear to be permanent in animals with BVH. Current concepts of the compensatory mechanisms in humans with BVH are largely inferential, as there is a lack of data from patients early in the disease process. Translation of animal studies of compensation for BVH into therapeutic strategies and subsequent application in the clinic is the most likely route to improve treatment. In addition to physical therapy, two types of prosthetic devices have been proposed to treat individuals with bilateral loss of vestibular inputs: those that provide tactile stimulation to indicate body position in space, and those that deliver electrical stimuli to branches of the vestibular nerve in accordance with head movements. The relative efficacy of these two treatment paradigms, and whether they can be combined to facilitate recovery, is yet to be ascertained

Plasticity in transmission strategies of the malaria parasite, Plasmodium chabaudi : environmental and genetic effects

Parasites may alter their behaviour to cope with changes in the within-host environment. In particular, investment in transmission may alter in response to the availability of parasite resources or host immune responses. However, experimental and theoretical studies have drawn conflicting conclusions regarding parasites' optimal (adaptive) responses to deterioration in habitat quality. We analyse data from acute infections with six genotypes of the rodent malaria species to quantify how investment in transmission (gametocytes) is influenced by the within-host environment. Using a minimum of modelling assumptions, we find that proportional investment in gametocytogenesis increases sharply with host anaemia and also increases at low parasite densities. Further, stronger dependence of investment on parasite density is associated with greater virulence of the parasite genotype. Our study provides a robust quantitative framework for studying parasites' responses to the host environment and whether these responses are adaptive, which is crucial for predicting the short-term and evolutionary impact of transmission-blocking treatments for parasitic diseases

Should we ban gasoline cars?

As electric vehicles become commercially viable, they have the potential to yield dramatic reductions in air pollution. The UK plans to have no gasoline vehicles by 2030, Norway by 2025, and California by 2035. But what is the best policy to achieve that? Is banning an effective option? Stephen P. Holland, Erin T. Mansur, and Andrew J. Yates provide a framework for assessing costs and benefits, elucidating key unknown parameters, and designing effective policies to discourage the use of gasoline

Metabolomic Profiling to Identify Predictors of Response to Vitamin E for Non-Alcoholic Steatohepatitis (NASH)

Vitamin E was recently shown to improve hepatic histology in a randomized controlled trial of pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS). The current study utilized samples collected in the PIVENS trial to identify: (1) baseline metabolomic profiles that could identify who would respond to vitamin E treatment and (2) end of treatment metabolomic profiles reflective of histologic improvement. A comprehensive analysis of metabolomics profiles (n = 547) quantified by mass spectrometry was performed in vitamin E responders (n = 16), vitamin E non-responders (n = 15), and placebo responders (n = 15). At baseline, phenyl-propionic acid (Odds ratio: 29.4, p\u3c0.01), indole-propionic acid levels (Odds ratio: 16.2, p\u3c0.01) were directly associated with a subsequent histologic response to vitamin E treatment whereas γ-carboxyethylhydroxychroman (CEHC) levels were inversely related to histologic response. Adjusting for baseline values by analysis of covariance, the end of treatment levels of gamma-glutamyl leucine (Fold change: 0.82, p\u3c0.02) and gamma-glutamyl valine (Fold change: 0.8, p\u3c0.03) were significantly lower in vitamin E responders compared to non-responders. The levels of gamma-glutamyl transpeptidase were not significantly different across the two groups. Subjects receiving placebo who demonstrated a histologic improvement also demonstrated lower levels of gamma-glutamylated amino acids (leucine, valine and isoleucine) compared to vitamin E non-responders. These data provide exploratory proof that there are measurable differences in the metabolic profile of subjects who are likely (vs unlikely) to respond to vitamin E treatment for NASH and in those experiencing histologic improvement (vs no improvement) on treatment and support further studies to validate these biomarkers