Sexual dimorphism in immunity across animals: a meta-analysis.

In animals, sex differences in immunity are proposed to shape variation in infection prevalence and intensity among individuals in a population, with females typically expected to exhibit superior immunity due to life-history trade-offs. We performed a systematic meta-analysis to investigate the magnitude and direction of sex differences in immunity and to identify factors that shape sex-biased immunocompetence. In addition to considering taxonomic and methodological effects as moderators, we assessed age-related effects, which are predicted to occur if sex differences in immunity are due to sex-specific resource allocation trade-offs with reproduction. In a meta-analysis of 584 effects from 124 studies, we found that females exhibit a significantly stronger immune response than do males, but the effect size is relatively small, and became non-significant after controlling for phylogeny. Female-biased immunity was more pronounced in adult than immature animals. More recently published studies did not report significantly smaller effect sizes. Among taxonomic and methodological subsets of the data, some of the largest effect sizes were in insects, further supporting previous suggestions that testosterone is not the only potential driver of sex differences in immunity. Our findings challenge the notion of pervasive biases towards female-biased immunity and the role of testosterone in driving these differences.

Androgens predict parasitism in female meerkats: a new perspective on a classic trade-off.

The immunocompetence handicap hypothesis posits that androgens in males can be a 'double-edged sword', actively promoting reproductive success, while also negatively impacting health. Because there can be both substantial androgen concentrations in females and significant androgenic variation among them, particularly in species portraying female social dominance over males or intense female-female competition, androgens might also play a role in mediating female health and fitness. We examined this hypothesis in the meerkat (Suricata suricatta), a cooperatively breeding, social carnivoran characterized by aggressively mediated female social dominance and extreme rank-related reproductive skew. Dominant females also have greater androgen concentrations and harbour greater parasite loads than their subordinate counterparts, but the relationship between concurrent androgen concentrations and parasite burdens is unknown. We found that a female's faecal androgen concentrations reliably predicted her concurrent state of endoparasitism irrespective of her social status: parasite species richness and infection by Spirurida nematodes, Oxynema suricattae, Pseudandrya suricattae and coccidia were greater with greater androgen concentrations. Based on gastrointestinal parasite burdens, females appear to experience the same trade-off in the costs and benefits of raised androgens as do the males of many species. This trade-off presumably represents a health cost of sexual selection operating in females.

Repetitive peptide boosting progressively enhances functional memory CTLs.

Cytotoxic T lymphocytes (CTLs) play a critical role in controlling intracellular pathogens and cancer cells, and induction of memory CTLs holds promise for developing effective vaccines against critical virus infections. However, generating memory CTLs remains a major challenge for conventional vector-based, prime-boost vaccinations. Thus, it is imperative that we explore nonconventional alternatives, such as boosting without vectors. We show here that repetitive intravenous boosting with peptide and adjuvant generates memory CD8 T cells of sufficient quality and quantity to protect against infection in mice. The resulting memory CTLs possess a unique and long-lasting effector memory phenotype, characterized by decreased interferon-γ but increased granzyme B production. These results are observed in both transgenic and endogenous models. Overall, our findings have important implications for future vaccine development, as they suggest that intravenous peptide boosting with adjuvant following priming can induce long-term functional memory CTLs.

Social and endocrine correlates of immune function in meerkats: implications for the immunocompetence handicap hypothesis.

Social status can mediate effects on the immune system, with profound consequences for individual health; nevertheless, most investigators of status-related disparities in free-ranging animals have used faecal parasite burdens to proxy immune function in the males of male-dominant species. We instead use direct measures of innate immune function (complement and natural antibodies) to examine status-related immunocompetence in both sexes of a female-dominant species. The meerkat is a unique model for such a study because it is a cooperatively breeding species in which status-related differences are extreme, evident in reproductive skew, morphology, behaviour, communication and physiology, including that dominant females naturally express the greatest total androgen (androstenedione plus testosterone) concentrations. We found that, relative to subordinates, dominant animals had reduced serum bacteria-killing abilities; also, relative to subordinate females, dominant females had reduced haemolytic complement activities. Irrespective of an individual's sex or social status, androstenedione concentrations (but not body condition, age or reproductive activity) negatively predicted concurrent immunocompetence. Thus, dominant meerkats of both sexes are immunocompromised. Moreover, in female meerkats, androstenedione perhaps acting directly or via local conversion, may exert a double-edged effect of promoting dominance and reproductive success at the cost of increased parasitism and reduced immune function. Given the prominent signalling of dominance in female meerkats, these findings may relate to the immunocompetence handicap hypothesis (ICHH); however, our data would suggest that the endocrine mechanism underlying the ICHH need not be mediated solely by testosterone and might explain trade-offs in females, as well as in males.

Production and Use of Hymenolepis diminuta Cysticercoids as Anti-Inflammatory Therapeutics.

Helminthic therapy has shown considerable promise as a means of alleviating some inflammatory diseases that have proven resistant to pharmaceutical intervention. However, research in the field has been limited by a lack of availability to clinician scientists of a helminth that is relatively benign, non-communicable, affordable, and effectively treats disease. Previous socio-medical studies have found that some individuals self-treating with helminths to alleviate various diseases are using the rat tapeworm (cysticercoid developmental stage of Hymenolepis diminuta; HDC). In this study, we describe the production and use of HDCs in a manner that is based on reports from individuals self-treating with helminths, individuals producing helminths for self-treatment, and physicians monitoring patients that are self-treating. The helminth may fit the criteria needed by clinical scientists for clinical trials, and the methodology is apparently feasible for any medical center to reproduce. It is hoped that future clinical trials using this organism may shed light on the potential for helminthic therapy to alleviate inflammatory diseases. Further, it is hoped that studies with HDCs may provide a stepping stone toward population-wide restoration of the biota of the human body, potentially reversing the inflammatory consequences of biota depletion that currently affect Western society.

Mix it and fix it: functions of composite olfactory signals in ring-tailed lemurs.

Animals communicating via scent often deposit composite signals that incorporate odorants from multiple sources; however, the function of mixing chemical signals remains understudied. We tested both a 'multiple-messages' and a 'fixative' hypothesis of composite olfactory signalling, which, respectively, posit that mixing scents functions to increase information content or prolong signal longevity. Our subjects-adult, male ring-tailed lemurs (Lemur catta)-have a complex scent-marking repertoire, involving volatile antebrachial (A) secretions, deposited pure or after being mixed with a squalene-rich paste exuded from brachial (B) glands. Using behavioural bioassays, we examined recipient responses to odorants collected from conspecific strangers. We concurrently presented pure A, pure B and mixed A + B secretions, in fresh or decayed conditions. Lemurs preferentially responded to mixed over pure secretions, their interest increasing and shifting over time, from sniffing and countermarking fresh mixtures, to licking and countermarking decayed mixtures. Substituting synthetic squalene (S)-a well-known fixative-for B secretions did not replicate prior results: B secretions, which contain additional chemicals that probably encode salient information, were preferred over pure S. Whereas support for the 'multiple-messages' hypothesis underscores the unique contribution from each of an animal's various secretions, support for the 'fixative' hypothesis highlights the synergistic benefits of composite signals.

Exceptional endocrine profiles characterise the meerkat: sex, status, and reproductive patterns.

In vertebrates, reproductive endocrine concentrations are strongly differentiated by sex, with androgen biases typifying males and estrogen biases typifying females. These sex differences can be reduced in female-dominant species; however, even the most masculinised of females have less testosterone (T) than do conspecific males. To test if aggressively dominant, female meerkats (Suricata suricatta) may be hormonally masculinised, we measured serum androstenedione (A4), T and estradiol (E2) in both sexes and social classes, during both 'baseline' and reproductive events. Relative to resident males, dominant females had greater A4, equivalent T and greater E2 concentrations. Males, whose endocrine values did not vary by social status, experienced increased T during reproductive forays, linking T to sexual behaviour, but not social status. Moreover, substantial E2 concentrations in male meerkats may facilitate their role as helpers. In females, dominance status and pregnancy magnified the unusual concentrations of measured sex steroids. Lastly, faecal androgen metabolites replicated the findings derived from serum, highlighting the female bias in total androgens. Female meerkats are thus strongly hormonally masculinised, possibly via A4's bioavailability for conversion to T. These raised androgen concentrations may explain female aggressiveness in this species and give dominant breeders a heritable mechanism for their daughters' competitive edge.

TLR agonists are highly effective at eliciting functional memory CTLs of effector memory phenotype in peptide immunization.

Given the importance of memory cytotoxic T lymphocytes (CTLs) in eliminating altered self-cells, including virus-infected and tumor cells, devising effective vaccination strategies for generating memory CTLs is a priority in the field of immunology. Herein, we elaborate upon a novel boosting approach that utilizes synthetic peptides and Toll-like receptor (TLR) agonists as adjuvants to generate sufficient numbers of memory CTLs to protect against infection in mice. Peptide boosting with lipopolysaccharide (LPS), a TLR4-ligand, has been shown to progressively enhance memory CTLs. Whether this result is strictly dependent on activation of TLR4 or can be similarly achieved by signaling through other TLRs is of practical interest in vaccine development but is yet unknown. In this report, we present evidence that intravenous peptide boosting together with TLR3 and TLR9 agonists (Poly IC and CpG, respectively) is highly effective and induces large quantities of memory CTLs of effector memory phenotype after three boosts. Compared to LPS, CpG and Poly IC generate more robust immune responses after the first and second boosts, indicating that a protective level of CTLs might be achieved with fewer boosts when CpG or Poly IC is used. Lastly, the resultant memory CTLs from boosting with different TLR agonists as adjuvant are equally protective against pathogen challenge and are not immune senescent. Therefore, TLR agonists are effective adjuvants in intravenous peptide boosting for the generation of functional memory CTLs.

Wnt signaling inhibits CTL memory programming.

Induction of functional CTLs is one of the major goals for vaccine development and cancer therapy. Inflammatory cytokines are critical for memory CTL generation. Wnt signaling is important for CTL priming and memory formation, but its role in cytokine-driven memory CTL programming is unclear. We found that wnt signaling inhibited IL-12-driven CTL activation and memory programming. This impaired memory CTL programming was attributed to up-regulation of eomes and down-regulation of T-bet. Wnt signaling suppressed the mTOR pathway during CTL activation, which was different to its effects on other cell types. Interestingly, the impaired memory CTL programming by wnt was partially rescued by mTOR inhibitor rapamycin. In conclusion, we found that crosstalk between wnt and the IL-12 signaling inhibits T-bet and mTOR pathways and impairs memory programming which can be recovered in part by rapamycin. In addition, direct inhibition of wnt signaling during CTL activation does not affect CTL memory programming. Therefore, wnt signaling may serve as a new tool for CTL manipulation in autoimmune diseases and immune therapy for certain cancers.

Nicotine inhibits memory CTL programming.

Nicotine is the main tobacco component responsible for tobacco addiction and is used extensively in smoking and smoking cessation therapies. However, little is known about its effects on the immune system. We confirmed that multiple nicotinic receptors are expressed on mouse and human cytotoxic T lymphocytes (CTLs) and demonstrated that nicotinic receptors on mouse CTLs are regulated during activation. Acute nicotine presence during activation increases primary CTL expansion in vitro, but impairs in vivo expansion after transfer and subsequent memory CTL differentiation, which reduces protection against subsequent pathogen challenges. Furthermore, nicotine abolishes the regulatory effect of rapamycin on memory CTL programming, which can be attributed to the fact that rapamycin enhances expression of nicotinic receptors. Interestingly, naïve CTLs from chronic nicotine-treated mice have normal memory programming, which is impaired by nicotine during activation in vitro. In conclusion, simultaneous exposure to nicotine and antigen during CTL activation negatively affects memory development.