Project description:Genes of the major histocompatibility complex (MHC) have been shown to influence social signalling and mate preferences in many species, including humans. First observations suggest that MHC signalling may also affect female fertility. To test this hypothesis, we exposed 191 female horses (Equus caballus) to either an MHC-similar or an MHC-dissimilar stimulus male around the time of ovulation and conception. A within-subject experimental design controlled for non-MHC-linked male characteristics, and instrumental insemination with semen of other males (n = 106) controlled for potential confounding effects of semen or embryo characteristics. We found that females were more likely to become pregnant if exposed to an MHC-dissimilar than to an MHC-similar male, while overall genetic distance to the stimulus males (based on microsatellite markers on 20 chromosomes) had no effect. Our results demonstrate that early pregnancy failures can be due to maternal life-history decisions (cryptic female choice) influenced by MHC-linked social signalling.
Project description:Many animals are known to preferentially mate with partners that are dissimilar at the major histocompatibility complex (MHC) in order to maximize the antigen binding repertoire (or disease resistance) in their offspring. Although several mammals, fish or lizards use odour cues to assess MHC similarity with potential partners, the ability of birds to assess MHC similarity using olfactory cues has not yet been explored. Here we used a behavioural binary choice test and high-throughput-sequencing of MHC class IIB to determine whether blue petrels can discriminate MHC similarity based on odour cues alone. Blue petrels are seabirds with particularly good sense of smell, they have a reciprocal mate choice and are known to preferentially mate with MHC-dissimilar partners. Incubating males preferentially approached the odour of the more MHC-dissimilar female, whereas incubating females showed opposite preferences. Given their mating pattern, females were, however, expected to show preference for the odour of the more MHC-dissimilar male. Further studies are needed to determine whether, as in women and female mice, the preference varies with the reproductive cycle in blue petrel females. Our results provide the first evidence that birds can use odour cues only to assess MHC dissimilarity.
Project description:The major histocompatibility complex (MHC) is a core part of the adaptive immune system. As in other vertebrate taxa, it may also affect human chemical communication via odour-based mate preferences, with greater attraction towards MHC-dissimilar partners. However, despite some well-known findings, the available evidence is equivocal and made complicated by varied approaches to quantifying human mate choice. To address this, we here conduct comprehensive meta-analyses focusing on studies assessing: (i) genomic mate selection, (ii) relationship satisfaction, (iii) odour preference, and (iv) all studies combined. Analysis of genomic studies reveals no association between MHC-dissimilarity and mate choice in actual couples; however, MHC effects appear to be independent of the genomic background. The effect of MHC-dissimilarity on relationship satisfaction was not significant, and we found evidence for publication bias in studies on this area. There was also no significant association between MHC-dissimilarity and odour preferences. Finally, combining effect sizes from all genomic, relationship satisfaction, odour preference and previous mate choice studies into an overall estimate showed no overall significant effect of MHC-similarity on human mate selection. Based on these findings, we make a set of recommendations for future studies, focusing both on aspects that should be implemented immediately and those that lurk on the far horizon. We need larger samples with greater geographical and cultural diversity that control for genome-wide similarity. We also need more focus on mechanisms of MHC-associated odour preferences and on MHC-associated pregnancy loss. This article is part of the Theo Murphy meeting issue 'Olfactory communication in humans'.
Project description:Cancers often relapse after adoptive therapy, even though specific T cells kill cells from the same cancer efficiently in vitro. We found that tumor eradication by T cells required high affinities of the targeted peptides for major histocompatibility complex (MHC) class I. Affinities of at least 10 nM were required for relapse-free regression. Only high-affinity peptide-MHC interactions led to efficient cross-presentation of antigen, thereby stimulating cognate T cells to secrete cytokines. These findings highlight the importance of targeting peptides with high affinity for MHC class I when designing T cell-based immunotherapy.
Project description:Ruminants are critical as prey in transferring solar energy fixed by plants into carnivorous species, yet the genetic signature of the driving forces leading to the evolutionary success of the huge number of ruminant species remains largely unknown. Here we report a complete DNA map of the major histocompatibility complex (MHC) of the addax (Addax nasomaculatus) genome by sequencing a total of 47 overlapping BAC clones previously mapped to cover the MHC region. The addax MHC is composed of 3,224,151 nucleotides, harboring a total of 150 coding genes, 50 tRNA genes, and 14 non-coding RNA genes. The organization of addax MHC was found to be highly conserved to those of sheep and cattle, highlighted by a large piece of chromosome inversion that divided the MHC class II into IIa and IIb subregions. It is now highly possible that all of the ruminant species in the family of Bovidae carry the same chromosome inversion in the MHC region, inherited from a common ancestor of ruminants. Phylogenetic analysis indicated that DY, a ruminant-specific gene located at the boundary of the inversion and highly expressed in dendritic cells, was possibly evolved from DQ, with an estimated divergence time ~140 million years ago. Homology modeling showed that the overall predicted structure of addax DY was similar to that of HLA-DQ2. However, the pocket properties of P1, P4, P6, and P9, which were critical for antigen binding in the addax DY, showed certain distinctive features. Structural analysis suggested that the populations of peptide antigens presented by addax DY and HLA-DQ2 were quite diverse, which in theory could serve to promote microbial regulation in the rumen by ruminant species, contributing to enhanced grass utilization ability. In summary, the results of our study helped to enhance our understanding of the MHC evolution and provided additional supportive evidence to our previous hypothesis that an ancient chromosome inversion in the MHC region of the last common ancestor of ruminants may have contributed to the evolutionary success of current ruminants on our planet.
Project description:Females are thought to gain better-quality genes for their offspring by mating with particular males. Genes of the major histocompatibility complex (MHC) play a critical role in adaptive immunity, and several studies have examined female mate choice in relation to MHC variation. In common yellowthroats, females prefer males that have larger black facial masks, an ornament associated with MHC variation, immune function and condition. Here we also tested whether mating patterns are directly correlated with MHC diversity or similarity. Using pyrosequencing, we found that the presence of extra-pair young in the brood was not related to male MHC diversity or similarity between the female and her within-pair mate. Furthermore, extra-pair sires did not differ in overall diversity from males they cuckolded, or in their similarity to the female. MHC diversity is extremely high in this species, and it may limit the ability of females to assess MHC variation in males. Thus, mating may be based on ornaments, such as mask size, which are better indicators of overall male health and genetic quality.
Project description:The alphabeta T cell receptor (TCR) is responsible for recognizing peptides bound and "presented" by major histocompatibility complex (MHC) molecules. We recently reported that at 25 degrees C the A6 TCR, which recognizes the Tax peptide presented by the class I MHC human leukocyte antigen-A*0201 (HLA-A2), binds with a weak DeltaH degrees , a favorable DeltaS degrees , and a moderately negative DeltaC(p). These observations were of interest given the unfavorable binding entropies and large heat capacity changes measured for many other TCR-ligand interactions, suggested to result from TCR conformational changes occurring upon binding. Here, we further investigated the A6-Tax/HLA-A2 interaction using titration calorimetry. We found that binding results in a pK(a) shift, complicating interpretation of measured binding thermodynamics. To better characterize the interaction, we measured binding as a function of pH, temperature, and buffer ionization enthalpy. A global analysis of the resulting data allowed determination of both the intrinsic binding thermodynamics separated from the influence of protonation as well as the thermodynamics associated with the pK(a) shift. Our results indicate that intrinsically, A6 binds Tax/HLA-A2 with a very weak DeltaH degrees , an even more favorable DeltaS degrees than previously thought, and a relatively large negative DeltaC(p). Comparison of these energetics with the makeup of the protein-protein interface suggests that conformational adjustments are required for binding, but these are more likely to be structural shifts, rather than disorder-to-order transitions. The thermodynamics of the pK(a) shift suggest protonation may be linked to an additional process such as ion binding.
Project description:The major histocompatibility complex (MHC) influences sexual selection in various vertebrates. Recently, MHC-linked social signaling was also shown to influence female fertility in horses (Equus caballus) diagnosed 17 days after fertilization. However, it remained unclear at which stage the pregnancy was terminated. Here we test if MHC-linked cryptic female choice in horses happens during the first days of pregnancy, i.e., until shortly after embryonic entrance into the uterus and before fixation in the endometrium. We exposed estrous mares to one of several unrelated stallions, instrumentally inseminated them with semen of another stallion, and flushed the uterus 8 days later to test for the presence of embryos. In total 68 embryos could be collected from 97 experimental trials. This success rate of 70.1% was significantly different from the mean pregnancy rate of 45.7% observed 17 days after fertilization using the same experimental protocol but without embryo flushing. Embryo recovery rate was not significantly dependent on whether the mares had been socially exposed to an MHC-dissimilar or an MHC-similar stallion. These observations suggest that MHC-linked maternal strategies affect embryo survival mainly (or only) during the time of fixation in the uterus.
Project description:T cells recognize antigens at the two-dimensional (2D) interface with antigen-presenting cells (APCs), which trigger T-cell effector functions. T-cell functional outcomes correlate with 2D kinetics of membrane-embedded T-cell receptors (TCRs) binding to surface-tethered peptide-major histocompatibility complex molecules (pMHCs). However, most studies have measured TCR-pMHC kinetics for recombinant TCRs in 3D by surface plasmon resonance, which differs drastically from 2D measurements. Here, we compared pMHC dissociation from native TCR on the T-cell surface to recombinant TCR immobilized on glass surface or in solution. Force on TCR-pMHC bonds regulated their lifetimes differently for native than recombinant TCRs. Perturbing the cellular environment suppressed 2D on-rates but had no effect on 2D off-rate regardless of whether force was applied. In contrast, for the TCR interacting with its monoclonal antibody, the 2D on-rate was insensitive to cellular perturbations and the force-dependent off-rates were indistinguishable for native and recombinant TCRs. These data present novel features of TCR-pMHC kinetics that are regulated by the cellular environment, underscoring the limitations of 3D kinetics in predicting T-cell functions and calling for further elucidation of the underlying molecular and cellular mechanisms that regulate 2D kinetics in physiological settings.