CD4+Foxp3+ regulatory T cells prolong drug-induced disease remission in (NZBxNZW) F1 lupus mice

Introduction

The ability to ameliorate murine lupus renders regulatory T cells (Treg) a promising tool for the treatment of systemic lupus erythematosus (SLE). In consideration to the clinical translation of a Treg-based immunotherapy of SLE, we explored the potential of CD4+Foxp3+ Treg to maintain disease remission after induction of remission with an established cyclophosphamide (CTX) regimen in lupus-prone (NZBxNZW) F1 mice. As a prerequisite for this combined therapy, we also investigated the impact of CTX on the biology of endogenous Treg and conventional CD4+ T cells (Tcon).

Methods

Remission of disease was induced in diseased (NZBxNZW) F1 mice with an established CTX regimen consisting of a single dose of glucocorticosteroids followed by five day course with daily injections of CTX. Five days after the last CTX injection, differing amounts of purified CD4+Foxp3+CD25+ Treg were adoptively transferred and clinical parameters, autoantibody titers, the survival and changes in peripheral blood lymphocyte subsets were determined at different time points during the study. The influence of CTX on the numbers, frequencies and proliferation of endogenous Treg and Tcon was analyzed in lymphoid organs by flow cytometry.

Results

Apart from abrogating the proliferation of Tcon, we found that treatment with CTX induced also a significant inhibition of Treg proliferation and a decline in Treg numbers in lymphoid organs. Additional adoptive transfer of 1.5 × 10⁶ purified Treg after the CTX regimen significantly increased the survival and prolonged the interval of remission by approximately five weeks compared to mice that received only the CTX regimen. The additional clinical amelioration was associated with an increase in the Treg frequency in the peripheral blood indicating a compensation of CTX-induced Treg deficiency by the Treg transfer.

Conclusions

Treg were capable to prolong the interval of remission induced by conventional cytostatic drugs. This study provides valuable information and a first proof-of-concept for the feasibility of a Treg-based immunotherapy in the maintenance of disease remission in SLE.     

Phenotypic and Evolutionary Consequences of Social Behaviours: Interactions among Individuals Affect Direct Genetic Effects

Traditional quantitative genetics assumes that an individual''s phenotype is determined by both genetic and environmental factors. For many animals, part of the environment is social and provided by parents and other interacting partners. When expression of genes in social partners affects trait expression in a focal individual, indirect genetic effects occur. In this study, we explore the effects of indirect genetic effects on the magnitude and range of phenotypic values in a focal individual in a multi-member model analyzing three possible classes of interactions between individuals. We show that social interactions may not only cause indirect genetic effects but can also modify direct genetic effects. Furthermore, we demonstrate that both direct and indirect genetic effects substantially alter the range of phenotypic values, particularly when a focal trait can influence its own expression via interactions with traits in other individuals. We derive a function predicting the relative importance of direct versus indirect genetic effects. Our model reveals that both direct and indirect genetic effects can depend to a large extent on both group size and interaction strength, altering group mean phenotype and variance. This may lead to scenarios where between group variation is much higher than within group variation despite similar underlying genetic properties, potentially affecting the level of selection. Our analysis highlights key properties of indirect genetic effects with important consequences for trait evolution, the level of selection and potentially speciation.     

RELATIVE CONTRIBUTION OF ADDITIVE, DOMINANCE, AND IMPRINTING EFFECTS TO PHENOTYPIC VARIATION IN BODY SIZE AND GROWTH BETWEEN DIVERGENT SELECTION LINES OF MICE

Epigenetic effects attributed to genomic imprinting are increasingly recognized as an important source of variation in quantitative traits. However, little is known about their relative contribution to phenotypic variation compared to those of additive and dominance effects, and almost nothing about their role in phenotypic evolution. Here we address these questions by investigating the relative contribution of additive, dominance, and imprinting effects of quantitative trait loci (QTL) to variation in "early" and "late" body weight in an intercross of mice selected for divergent adult body weight. We identified 18 loci on 13 chromosomes; additive effects accounted for most of the phenotypic variation throughout development, and imprinting effects were always small. Genetic effects on early weight showed more dominance, less additive, and, surprisingly, less imprinting variation than that of late weight. The predominance of additivity of QTL effects on body weight follows the expectation that additive effects account for the evolutionary divergence between selection lines. We hypothesize that the appearance of more imprinting effects on late body weight may be a consequence of divergent selection on adult body weight, which may have indirectly selected for alleles showing partial imprinting effects due to their associated additive effects, highlighting a potential role of genomic imprinting in the response to selection.     

A Maternal–Offspring Coadaptation Theory for the Evolution of Genomic Imprinting

Imprinted genes are expressed either from the maternally or paternally inherited copy only, and they play a key role in regulating complex biological processes, including offspring development and mother–offspring interactions. There are several competing theories attempting to explain the evolutionary origin of this monoallelic pattern of gene expression, but a prevailing view has emerged that holds that genomic imprinting is a consequence of conflict between maternal and paternal gene copies over maternal investment. However, many imprinting patterns and the apparent overabundance of maternally expressed genes remain unexplained and may be incompatible with current theory. Here we demonstrate that sole expression of maternal gene copies is favored by natural selection because it increases the adaptive integration of offspring and maternal genomes, leading to higher offspring fitness. This novel coadaptation theory for the evolution of genomic imprinting is consistent with results of recent studies on epigenetic effects, and it provides a testable hypothesis for the origin of previously unexplained major imprinting patterns across different taxa. In conjunction with existing hypotheses, our results suggest that imprinting may have evolved due to different selective pressures at different loci.     

Indiscriminate nursing in communal breeders: a role for genomic imprinting

Abstract In several communally nesting mammal species, females indiscriminately nurse each others' offspring. Previous hypotheses have suggested that the inability to recognize one's own young during lactation is the result of costs incurred from recognition errors. Here, we propose an alternative hypothesis based on sexual conflict theory and genomic imprinting. In polygynous species, males copulate with several females that may later breed communally. Under such conditions, males benefit from indiscriminate nursing of all their offspring and the reduced risk of female infanticide. This may have selected for paternally expressed genes that suppress kin recognition during lactation.     

Green beards in the light of indirect genetic effects

The green‐beard effect is one proposed mechanism predicted to underpin the evolution of altruistic behavior. It relies on the recognition and the selective help of altruists to each other in order to promote and sustain altruistic behavior. However, this mechanism has often been dismissed as unlikely or uncommon, as it is assumed that both the signaling trait and altruistic trait need to be encoded by the same gene or through tightly linked genes. Here, we use models of indirect genetic effects (IGEs) to find the minimum correlation between the signaling and altruistic trait required for the evolution of the latter. We show that this correlation threshold depends on the strength of the interaction (influence of the green beard on the expression of the altruistic trait), as well as the costs and benefits of the altruistic behavior. We further show that this correlation does not necessarily have to be high and support our analytical results by simulations.     

Maternal effects as the cause of parent-of-origin effects that mimic genomic imprinting

Epigenetic effects are increasingly recognized as an important source of variation in complex traits and have emerged as the focus of a rapidly expanding area of research. Principle among these effects is genomic imprinting, which has generally been examined in analyses of complex traits by testing for parent-of-origin-dependent effects of alleles. However, in most of these analyses maternal effects are confounded with genomic imprinting because they can produce the same patterns of phenotypic variation expected for various forms of imprinting. Distinguishing between the two is critical for genetic and evolutionary studies because they have entirely different patterns of gene expression and evolutionary dynamics. Using a simple single-locus model, we show that maternal genetic effects can result in patterns that mimic those expected under genomic imprinting. We further demonstrate how maternal effects and imprinting effects can be distinguished using genomic data from parents and offspring. The model results are applied to a genome scan for quantitative trait loci (QTL) affecting growth- and weight-related traits in mice to illustrate how maternal effects can mimic imprinting. This genome scan revealed five separate maternal-effect loci that caused a diversity of patterns mimicking those expected under various modes of genomic imprinting. These results demonstrate that the appearance of parent-of-origin-dependent effects (POEs) of alleles at a locus cannot be taken as direct evidence that the locus is imprinted. Moreover, they show that, in gene mapping studies, genetic data from both parents and offspring are required to successfully differentiate between imprinting and maternal effects as the cause of apparent parent-of-origin effects of alleles.     

Social Selection and Indirect Genetic Effects in Structured populations

Social selection and indirect genetic effects (IGEs) are established concepts in both behavioural ecology and evolutionary genetics. While IGEs describe effects of an individual’s genotype on phenotypes of social partners (and may thus affect their fitness indirectly), the concept of social selection assumes that a given phenotype in one individual affects the fitness of other individuals directly. Although different frameworks, both have been used to investigate the evolution of social traits, such as cooperative behaviour. Despite their similarities (both concepts consider interactions among individuals), they differ in the type of interaction. It remains unclear whether the two concepts make the same predictions about evolutionary trajectories or not. To address this question, we investigate four possible scenarios of social interactions and compare the effects of IGEs and social selection for trait evolution in a multi-trait multi-member model. We show that the two mechanisms can yield similar evolutionary outcomes and that both can create selection pressure at the group level. However, the effect of IGEs can be stronger due to the possibility of feedback loops. Finally, we demonstrate that IGEs, but not social selection gradients, may lead to differences in the direction of evolutionary response between genotypes and phenotypes.     

A maternal-offspring coadaptation theory for the evolution of genomic imprinting

Imprinted genes are expressed either from the maternally or paternally inherited copy only, and they play a key role in regulating complex biological processes, including offspring development and mother–offspring interactions. There are several competing theories attempting to explain the evolutionary origin of this monoallelic pattern of gene expression, but a prevailing view has emerged that holds that genomic imprinting is a consequence of conflict between maternal and paternal gene copies over maternal investment. However, many imprinting patterns and the apparent overabundance of maternally expressed genes remain unexplained and may be incompatible with current theory. Here we demonstrate that sole expression of maternal gene copies is favored by natural selection because it increases the adaptive integration of offspring and maternal genomes, leading to higher offspring fitness. This novel coadaptation theory for the evolution of genomic imprinting is consistent with results of recent studies on epigenetic effects, and it provides a testable hypothesis for the origin of previously unexplained major imprinting patterns across different taxa. In conjunction with existing hypotheses, our results suggest that imprinting may have evolved due to different selective pressures at different loci.     

Effects of Increased Spatial Complexity on Behavioural Development and Task Performance in Lister Hooded Rats

Enhancing laboratory animal welfare, particularly in rodents, has been achieved through environmental enrichment in caging systems. Traditional enrichment such as adding objects has shown to impact development, reproductive and maternal performance as well as cognition. However, effects of increased spatial complexity as part of larger novel caging systems have not been investigated. While adoption of caging systems with increased spatial complexity seems uncontroversial from a welfare perspective, effects of such housing on the development and task performance of experimental animals remains unclear. In this study, we investigate differences in key behaviours and cognitive performance between Lister Hooded rats housed in traditional (single-shelf) cages (‘basic’) and those housed in larger cages with an additional shelf (‘enriched’). We found minor differences in maternal behaviour, such as nursing and offspring development. Further, we compared task performance in females, using a hippocampus-dependent task (T-maze) and a hippocampus-independent task (Novel Object Recognition, NOR). While in the T-maze no differences in either the rate of learning or probe trial performance were found, in the NOR task females housed in enriched cages performed better than those housed in basic cages. Our results show that increased spatial complexity does not significantly affect development and maternal performance but may enhance learning in females for a non-spatial task. Increased spatial complexity does not appear to have the same effects on behaviour and development as traditional enrichment. Thus, our results suggest no effect of housing conditions on the development of most behaviours in experimental animals housed in spatially enriched caging systems.