Safety and clinical activity of autologous RNA chimeric antigen receptor T-cell therapy in myasthenia gravis (MG-001): a prospective, multicentre, open-label, non-randomised phase 1b/2a study.

BACKGROUND: Chimeric antigen receptor (CAR) T cells are highly effective in treating haematological malignancies, but associated toxicities and the need for lymphodepletion limit their use in people with autoimmune disease. To explore the use of CAR T cells for the treatment of people with autoimmune disease, and to improve their safety, we engineered them with RNA (rCAR-T)-rather than the conventional DNA approach-to target B-cell maturation antigen (BCMA) expressed on plasma cells. To test the suitability of our approach, we used rCAR-T to treat individuals with myasthenia gravis, a prototypical autoantibody disease mediated partly by pathogenic plasma cells. METHODS: MG-001 was a prospective, multicentre, open-label, phase 1b/2a study of Descartes-08, an autologous anti-BCMA rCAR-T therapy, in adults (ie, aged ≥18 years) with generalised myasthenia gravis and a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of 6 or higher. The study was done at eight sites (ie, academic medical centres or community neurology clinics) in the USA. Lymphodepletion chemotherapy was not used. In part 1 (phase 1b), participants with Myasthenia Gravis Foundation of America (MGFA) disease class III-IV generalised myasthenia gravis received three ascending doses of Descartes-08 to determine a maximum tolerated dose. In part 2 (phase 2a), participants with generalised myasthenia gravis with MGFA disease class II-IV received six doses at the maximum tolerated dose in an outpatient setting. The primary objective was to establish safety and tolerability of Descartes-08; secondary objectives were to assess myasthenia gravis disease severity and biomarkers in participants who received Descartes-08. This trial is registered with clinicaltrials.gov, NCT04146051. FINDINGS: We recruited 16 individuals for screening between Jan 7, 2020 and Aug 3, 2022. 14 participants were enrolled (n=3 in part 1, n=11 in part 2). Ten participants were women and four were men. Two individuals did not qualify due to low baseline MG-ADL score (n=1) or lack of generalised disease (n=1). Median follow-up in part 2 was 5 months (range 3-9 months). There was no dose-limiting toxicity, cytokine release syndrome, or neurotoxicity. Common adverse events were headache (six of 14 participants), nausea (five of 14), vomiting (three of 14), and fever (four of 14), which resolved within 24 h of infusion. Fevers were not associated with increased markers of cytokine release syndrome (IL-6, IL-2, and TNF). Mean improvements from baseline to week 12 were -6 (95% CI -9 to -3) for MG-ADL score, -7 (-11 to -3) for Quantitative Myasthenia Gravis score, -14 (-19 to -9) for Myasthenia Gravis Composite score, and -9 (-15 to -3) for Myasthenia Gravis Quality of Life 15-revised score. INTERPRETATION: In this first study of an rCAR-T therapy in individuals with an autoimmune disease, Descartes-08 appeared to be safe and was well tolerated. Descartes-08 infusions were followed by clinically meaningful decreases on myasthenia gravis severity scales at up to 9 months of follow-up. rCAR-T therapy warrants further investigation as a potential new treatment approach for individuals with myasthenia gravis and other autoimmune diseases. FUNDING: Cartesian Therapeutics and National Institute of Neurological Disorders and Stroke of the National Institutes of Health.

Dietary specialization is conditionally associated with increased ant predation risk in a temperate forest caterpillar community.

The enemy-free space hypothesis (EFSH) contends that generalist predators select for dietary specialization in insect herbivores. At a community level, the EFSH predicts that dietary specialization reduces predation risk, and this pattern has been found in several studies addressing the impact of individual predator taxa or guilds. However, predation at a community level is also subject to combinatorial effects of multiple-predator types, raising the question of how so-called multiple-predator effects relate to dietary specialization in insect herbivores. Here, we test the EFSH with a field experiment quantifying ant predation risk to insect herbivores (caterpillars) with and without the combined predation effects of birds. Assessing a community of 20 caterpillar species, we use model selection in a phylogenetic comparative framework to identify the caterpillar traits that best predict the risk of ant predation. A caterpillar species' abundance, dietary specialization, and behavioral defenses were important predictors of its ant predation risk. Abundant caterpillar species had increased risk of ant predation irrespective of bird predation. Caterpillar species with broad diet breadth and behavioral responsiveness to attack had reduced ant predation risk, but these ant effects only occurred when birds also had access to the caterpillar community. These findings suggest that ant predation of caterpillar species is density- or frequency-dependent, that ants and birds may impose countervailing selection on dietary specialization within the same herbivore community, and that contingent effects of multiple predators may generate behaviorally mediated life-history trade-offs associated with herbivore diet breadth.

Keystone mutualism influences forest tree growth at a landscape scale.

Interactions between ants and phloem-feeding herbivores are characterised as a keystone mutualism because they restructure arthropod communities and generate trophic cascades. Keystone interactions in terrestrial food webs are hypothesised to depend on herbivore community structure and bottom-up effects on plant growth. Here, we tested this prediction at a landscape scale with a long-term ant-exclusion experiment on hickory saplings in the context of spatial variation in herbivore community structure and habitat quality. We quantified top-down effects of ants, herbivore communities as well as abiotic factors impacting hickory shoot growth. We found that ants influenced shoot growth via strong, context-dependent, compensatory effects, with clear cascading benefits only when phloem-feeders were present and chewing herbivore abundance was high. By contrast, while several landscape variables predicted hickory growth, they did not mediate the strength of cascading effects of ants. These results suggest that ant/sap-feeder mutualisms may regulate forest productivity by mediating effects of multiple herbivore guilds.

Tritrophic niches of insect herbivores in an era of rapid environmental change.

A multi-trophic perspective improves understanding of the ecological and evolutionary consequences of rapid environmental change on insect herbivores. Loss of specialized enemies due to human impacts is predicted to dramatically reduce the number of tritrophic niches of herbivores compared to a bitrophic niche perspective. Habitat fragmentation and climate change promote the loss of both specialist enemies and herbivores, favoring ecological generalism across trophic levels. Species invasion can fundamentally alter trophic interactions toward various outcomes and contributes to ecological homogenization. Adaptive evolution on ecological timescales is expected to dampen tritrophic instabilities and diversify niches, yet its ability to compensate for tritrophic niche losses in the short term is unclear.

Anthropogenic fragmentation of landscapes: mechanisms for eroding the specificity of plant-herbivore interactions.

Reduced ecological specialization is an emerging, general pattern of ecological networks in fragmented landscapes. In plant-herbivore interactions, reductions in dietary specialization of herbivore communities are consistently associated with fragmented landscapes, but the causes remain poorly understood. We propose several hypothetical bottom-up and top-down mechanisms that may reduce the specificity of plant-herbivore interactions. These include empirically plausible applications and extensions of theory based on reduced habitat patch size and isolation (considered jointly), and habitat edge effects. Bottom-up effects in small, isolated habitat patches may limit availability of suitable hostplants, a constraint that increases with dietary specialization. Poor hostplant quality due to inbreeding in such fragments may especially disadvantage dietary specialist herbivores even when their hostplants are present. Size and isolation of habitat patches may change patterns of predation of herbivores, but whether such putative changes are associated with herbivore dietary specialization should depend on the mobility, size, and diet breadth of predators. Bottom-up edge effects may favor dietary generalist herbivores, yet top-down edge effects may favor dietary specialists owing to reduced predation. An increasingly supported edge effect is trophic ricochets generated by large grazers/browsers, which remove key hostplant species of specialist herbivores. We present empirical evidence that greater deer browsing in small forest fragments disproportionately reduces specialist abundances in lepidopteran assemblages in northeastern USA. Despite indirect evidence for these mechanisms, they have received scant direct testing with experimental approaches at a landscape scale. Identifying their relative contributions to reduced specificity of plant-herbivore interactions in fragmented landscapes is an important research goal.

Keystone mutualism strengthens top-down effects by recruiting large-bodied ants.

Determining the impacts of mutualistic interactions and predator diversity on food webs are two important goals in community ecology. In this study, we examined how predator community variation mediates the strength of top-down effects in the presence and absence of mutualistic interactions. We examined the impacts of predatory ant species that simultaneously prey on leaf-chewing herbivores (Lepidoptera) and engage in food-for-protection mutualisms with sap-feeding herbivores (Hemiptera) in the lower canopy of Connecticut forests. In this 2-year study, we examined three hypothetical mechanisms by which mutualisms can alter the top-down effects of ants: (1) sap feeders increase ant abundance, thus strengthening predatory effects; (2) sap feeders increase the relative abundance of a species that has stronger predatory effects; and (3) changes to predator diversity (species richness) are caused by sap feeders mediating top-down effects of the ant community. Experiments revealed that host plants occupied by sap feeders favored large-bodied ant species in the genus Camponotus, but there were no changes to community-wide ant abundance or ant species richness. Fitting predictions of predation strength based on the functional trait of body size, large-bodied Camponotus suppressed caterpillars and reduced leaf herbivory. This work shows that the ant-hemipteran mutualism, which has been characterized as a keystone interaction, can generate strong top-down effects on leaf-chewing herbivores and herbivory via increasing the relative abundance of species with functional traits relevant to predation, such as body size. Therefore, the emergence of specific ants as keystone predators in a community can be contingent upon their mutualism with sap-feeding Hemiptera.

Parasite-altered feeding behavior in insects: integrating functional and mechanistic research frontiers.

Research on parasite-altered feeding behavior in insects is contributing to an emerging literature that considers possible adaptive consequences of altered feeding behavior for the host or the parasite. Several recent ecoimmunological studies show that insects can adaptively alter their foraging behavior in response to parasitism. Another body of recent work shows that infection by parasites can change the behavior of insect hosts to benefit the parasite; manipulations of host feeding behavior may be part of this phenomenon. Here, we address both the functional and the underlying physiological frontiers of parasite-altered feeding behavior in order to spur research that better integrates the two. Functional categories of parasite-altered behavior that are adaptive for the host include prophylaxis, therapy and compensation, while host manipulation is adaptive for the parasite. To better understand and distinguish prophylaxis, therapy and compensation, further study of physiological feedbacks affecting host sensory systems is especially needed. For host manipulation in particular, research on mechanisms by which parasites control host feedbacks will be important to integrate with functional approaches. We see this integration as critical to advancing the field of parasite-altered feeding behavior, which may be common in insects and consequential for human and environmental health.

Predatory birds and ants partition caterpillar prey by body size and diet breadth.

The effects of predator assemblages on herbivores are predicted to depend critically on predator-predator interactions and the extent to which predators partition prey resources. The role of prey heterogeneity in generating such multiple predator effects has received limited attention. Vertebrate and arthropod insectivores constitute two co-dominant predatory taxa in many ecosystems, and the emergent properties of their joint effects on insect herbivores inform theory on multiple predator effects as well as biological control of insect herbivores. Here we use a large-scale factorial manipulation to assess the extent to which birds and ants engage in antagonistic predator-predator interactions and the consequences of heterogeneity in herbivore body size and diet breadth (i.e. the diversity of host plants used) for prey partitioning. We excluded birds and reduced ant density (by 60%) in the canopies of eight northeastern USA deciduous tree species during two consecutive years and measured the community composition and traits of lepidopteran larvae (caterpillars). Birds did not affect ant density, implying limited intraguild predation between these taxa in this system. Birds preyed selectively upon large-bodied caterpillars (reducing mean caterpillar length by 12%) and ants preyed selectively upon small-bodied caterpillars (increasing mean caterpillar length by 6%). Birds and ants also partitioned caterpillar prey by diet breadth. Birds reduced the frequency dietary generalist caterpillars by 24%, while ants had no effect. In contrast, ants reduced the frequency of dietary specialists by 20%, while birds had no effect, but these effects were non-additive; under bird exclusion, ants had no detectable effect, while in the presence of birds, they reduced the frequency of specialists by 40%. As a likely result of prey partitioning by body size and diet breadth, the combined effects of birds and ants on total caterpillar density were additive, with birds and ants reducing caterpillar density by 44% and 20% respectively. These results show evidence for the role of prey heterogeneity in driving functional complementarity among predators and enhanced top-down control. Heterogeneity in herbivore body size and diet breadth, as well as other prey traits, may represent key predictors of the strength of top-down control from predator communities.

Multiple interaction types determine the impact of ant predation of caterpillars in a forest community.

Direct and indirect effects of predators are highly variable in complex communities, and understanding the sources of this variation is a research priority in community ecology. Recent evidence indicates that herbivore community structure is a primary determinant of predation strength and its cascading impacts on plants. In this study, we use variation in herbivore community structure among plant species to experimentally test two hypotheses in a temperate forest food web. First, variation in the strength of predator effects, such as ant predation of caterpillars, is predicted to be density dependent, exhibiting stronger effects when prey abundance is high (density-dependent predation hypothesis). Second, mutualistic interactions between ants and sap-feeding herbivores are expected to increase the abundance of predatory ants, strengthening predation effects on herbivores with cascading effects on host plants (keystone mutualism hypothesis). Using a large-scale predator exclusion experiment across eight dominant tree species, we tracked changes in insect density on 862 plants across two years, recording 2,322 ants, 1,062 sap-feeders, 5,322 caterpillars, and quantifying herbivory on 199, 338 leaves. In this experiment, density-dependent predation did not explain variation in the direct or indirect effects of ants on caterpillars and herbivory. In partial support of the keystone mutualism hypothesis, sap-feeders strengthened top-down effects of ants on caterpillars under some conditions. However, stronger ant predation of caterpillars did not lead to measurable trophic cascades on trees occupied by sap-feeders. Instead, the presence of sap-feeders was associated with increased per capita feeding damage by caterpillars, and this bottom-up effect attenuated the indirect effects of ants on host plants. These findings demonstrate that examining the multi-trophic impacts of mutualisms and predation in the context of the broader community can reveal patterns otherwise masked by compensatory interactions.

Behaviorally plastic host-plant use by larval Lepidoptera in tri-trophic food webs.

Plant-insect interactions research emphasizes adaptive plasticity of plants and carnivores, such as parasitoids, implying a relatively passive role of herbivores. Current work is addressing this deficit, with exciting studies of behavioral plasticity of larval Lepidoptera (caterpillars). Here I use select examples to illustrate the diversity of behaviorally plastic host-plant use by caterpillars, including anti-predator tactics, self-medication, and evasion of dynamic plant defenses, as proof of the agency of caterpillar behavior in plant-insect interactions. I emphasize the significance of adaptive behavioral plasticity of caterpillars in the context of tri-trophic interactions. Recent research on trait-mediated indirect interactions places adaptive behavioral plasticity of herbivores at the center of community and food web dynamics, with far-reaching consequences of issues such as community stability.

The global distribution of diet breadth in insect herbivores.

Understanding variation in resource specialization is important for progress on issues that include coevolution, community assembly, ecosystem processes, and the latitudinal gradient of species richness. Herbivorous insects are useful models for studying resource specialization, and the interaction between plants and herbivorous insects is one of the most common and consequential ecological associations on the planet. However, uncertainty persists regarding fundamental features of herbivore diet breadth, including its relationship to latitude and plant species richness. Here, we use a global dataset to investigate host range for over 7,500 insect herbivore species covering a wide taxonomic breadth and interacting with more than 2,000 species of plants in 165 families. We ask whether relatively specialized and generalized herbivores represent a dichotomy rather than a continuum from few to many host families and species attacked and whether diet breadth changes with increasing plant species richness toward the tropics. Across geographic regions and taxonomic subsets of the data, we find that the distribution of diet breadth is fit well by a discrete, truncated Pareto power law characterized by the predominance of specialized herbivores and a long, thin tail of more generalized species. Both the taxonomic and phylogenetic distributions of diet breadth shift globally with latitude, consistent with a higher frequency of specialized insects in tropical regions. We also find that more diverse lineages of plants support assemblages of relatively more specialized herbivores and that the global distribution of plant diversity contributes to but does not fully explain the latitudinal gradient in insect herbivore specialization.

Enemy-free space for parasitoids.

Natural enemies often cause significant levels of mortality for their prey and thus can be important agents of natural selection. It follows, then, that selection should favor traits that enable organisms to escape from their natural enemies into "enemy-free space" (EFS). Natural selection for EFS was originally proposed as a general force in structuring ecological communities, but more recently has become conceptually narrow and is typically only invoked when studying the evolutionary ecology of host plant use by specialized insect herbivores. By confining the application of EFS to specialist herbivores, its potential value to community and evolutionary ecology has been marginalized. As a first step toward exploring the potential explanatory power of EFS in structuring ecological niches of higher trophic-level organisms, we consider host use by parasitoids. Here, we present three distinct mechanisms from our studies of caterpillar host-parasitoid interactions suggesting that parasitoids may be under selection to exploit traits of their hosts and the plants on which those hosts feed to garner EFS for their developing offspring. The neglect of EFS as a top-down selective force on host use by parasitoids may be a serious limitation to basic and applied ecology, given the great diversity of parasitoids and their significance in controlling herbivore populations in both natural and managed ecosystems. Parasitoids and other mesopredators represent excellent candidates for further developments of EFS theory and testing of its broader importance.

Herbivore diet breadth mediates the cascading effects of carnivores in food webs.

Predicting the impact of carnivores on plants has challenged community and food web ecologists for decades. At the same time, the role of predators in the evolution of herbivore dietary specialization has been an unresolved issue in evolutionary ecology. Here, we integrate these perspectives by testing the role of herbivore diet breadth as a predictor of top-down effects of avian predators on herbivores and plants in a forest food web. Using experimental bird exclosures to study a complex community of trees, caterpillars, and birds, we found a robust positive association between caterpillar diet breadth (phylodiversity of host plants used) and the strength of bird predation across 41 caterpillar and eight tree species. Dietary specialization was associated with increased enemy-free space for both camouflaged (n = 33) and warningly signaled (n = 8) caterpillar species. Furthermore, dietary specialization was associated with increased crypsis (camouflaged species only) and more stereotyped resting poses (camouflaged and warningly signaled species), but was unrelated to caterpillar body size. These dynamics in turn cascaded down to plants: a metaanalysis (n = 15 tree species) showed the beneficial effect of birds on trees (i.e., reduced leaf damage) decreased with the proportion of dietary specialist taxa composing a tree species' herbivore fauna. We conclude that herbivore diet breadth is a key functional trait underlying the trophic effects of carnivores on both herbivores and plants.

Ecological immunology mediated by diet in herbivorous insects.

A rapidly advancing area of ecological immunology concerns the effects of diet on animals' immunological responses to parasites and pathogens. Here, we focus on diet-mediated ecological immunology in herbivorous insects, in part because these organisms commonly experience nutritional limitations from their diets of plants. Nutritional immunology highlights nutrient-based trade-offs between immunological and other physiological processes as well as trade-offs among distinct immunological processes. This field reveals that nutrition influences the quality and quantity of immunological defense in herbivorous insects, and conversely that nutritional intake by herbivorous insects can be an adaptive response to the specific types of immune-challenge they face in the context of other physiological processes. Because the diets of herbivores challenge them physiologically with plants' secondary metabolites, another area of study analyzes constraints on immunological defense imposed by secondary metabolites of plants in the diets of herbivorous insects. Alternatively, some herbivores can use secondary metabolites as medicine against parasites or pathogens. Animal-medication theory makes an important contribution to ecological immunology by distinguishing prophylactic and therapeutic mechanisms of anti-parasite defense. Integrating ideas from animal-medication and nutritional immunology, we outline a conceptual framework in which the immunological role of the diet consists of mechanisms of prophylaxis, therapy, compensation, and combinations thereof. Then, we use this framework to organize findings from our own research on diet-mediated ecological immunology of woolly bear caterpillars. We show evidence that the woolly bear caterpillar, Grammia incorrupta (Hy. Edwards) (Lepidoptera, Erebidae, and Arctiinae), can employ both diet-mediated prophylaxis and therapy. First, increased consumption of carbohydrate-biased food prior to immune-challenge increased its melanization-response. Second, increased consumption of pyrrolizidine alkaloids (PAs) more than 24 h after parasitism by tachinid flies resulted in anti-parasite resistance. Caterpillars reduced feeding on protein-biased food within 24 h after immune-challenge, showing evidence of illness-induced anorexia. We synthesize our work to generate the hypothesis that a diet-mediated defense by the host against parasites acts as a temporally explicit, multi-stage process.

Reduced consumption of protein-rich foods follows immune challenge in a polyphagous caterpillar.

Advances in ecological immunity have illustrated that, like vertebrates, insects exhibit adaptive immunity, including induced changes in feeding behavior that aid the immune system. In particular, recent studies have pointed to the importance of protein intake in mounting an immune response. In this study, we tested the hypothesis that the polyphagous caterpillar Grammia incorrupta (H. Edwards) (Family: Erebidae) would adaptively change its feeding behavior in response to immune challenge, predicting that caterpillars would increase their intake of dietary protein. We further predicted that this response would enhance the melanization response, a component of the immune system that acts against parasitoids. We challenged the immune system using either tachinid fly parasitoids or a bead injection technique that has been used in studies to simulate parasitism, and measured feeding before and after immune challenge on diets varying in their macronutrient content. To evaluate the effects of diet on melanization, we quantified melanization of beads following feeding assays. Contrary to our prediction, we found that parasitized or injected caterpillars given a choice between high- and low-protein foods reduced their intake of the high-protein food. Furthermore, in a no-choice experiment, caterpillars offered food with a protein concentration that is optimal for growth reduced feeding following immune challenge, whereas those offered a low-protein food did not. Although variation in protein intake did not change the caterpillars' melanization response, increased carbohydrate intake did increase melanization, suggesting a prophylactic role for carbohydrates. We discuss alternative mechanisms by which variation in protein intake could negatively or positively affect parasitized caterpillars, including nutritional interactions with the caterpillar's self-medication response.

Can caterpillar density or host-plant quality explain host-plant-related parasitism of a generalist forest caterpillar assemblage?

Herbivore-carnivore interactions are influenced by the plants on which herbivores feed. Accordingly, dietary generalist herbivores have been shown to experience differential risk of mortality from carnivores on different host-plant species. Here, we investigate whether caterpillar density and host-plant quality play a role in driving variation in generalist forest caterpillar mortality from insect parasitoids using a large-scale, multi-year observational study. A total of 4,500 polyphagous caterpillars were collected from eight host-tree species in Connecticut deciduous forests over 5 years, and frequencies of mortality from insect parasitoids (flies and wasps) were compared across the eight host-plant species for the entire generalist caterpillar assemblage (76 species). Separate comparisons were made using seven numerically dominant generalist species, allowing us to account for variation in caterpillar species-specific parasitism risk. We find significant variation in parasitism frequencies of generalist caterpillars across the eight host-plant species when accounting for variation in caterpillar density. We find no support for an influence of caterpillar density on parasitism and no clear evidence for an effect of host-plant quality on parasitism. Therefore, the results of this study discount the hypotheses that variation in caterpillar density and host-plant quality are responsible for variation in parasitism frequencies across host-plant species. Instead, our findings point to other plant-related characteristics, such as plant-derived parasitoid attractants, which may have robust, community-wide effects.

The tri-trophic interactions hypothesis: interactive effects of host plant quality, diet breadth and natural enemies on herbivores.

Several influential hypotheses in plant-herbivore and herbivore-predator interactions consider the interactive effects of plant quality, herbivore diet breadth, and predation on herbivore performance. Yet individually and collectively, these hypotheses fail to address the simultaneous influence of all three factors. Here we review existing hypotheses, and propose the tri-trophic interactions (TTI) hypothesis to consolidate and integrate their predictions. The TTI hypothesis predicts that dietary specialist herbivores (as compared to generalists) should escape predators and be competitively dominant due to faster growth rates, and that such differences should be greater on low quality (as compared to high quality) host plants. To provide a preliminary test of these predictions, we conducted an empirical study comparing the effects of plant (Baccharis salicifolia) quality and predators between a specialist (Uroleucon macolai) and a generalist (Aphis gossypii) aphid herbivore. Consistent with predictions, these three factors interactively determine herbivore performance in ways not addressed by existing hypotheses. Compared to the specialist, the generalist was less fecund, competitively inferior, and more sensitive to low plant quality. Correspondingly, predator effects were contingent upon plant quality only for the generalist. Contrary to predictions, predator effects were weaker for the generalist and on low-quality plants, likely due to density-dependent benefits provided to the generalist by mutualist ants. Because the TTI hypothesis predicts the superior performance of specialists, mutualist ants may be critical to A. gossypii persistence under competition from U. macolai. In summary, the integrative nature of the TTI hypothesis offers novel insight into the determinants of plant-herbivore and herbivore-predator interactions and the coexistence of specialist and generalist herbivores.

Tritrophic interactions at a community level: effects of host plant species quality on bird predation of caterpillars.

Effects of plant traits on herbivore-carnivore interactions are well documented in component communities but are not well understood at the level of large, complex communities. We report on a 2-year field experiment testing mechanisms by which variation in food quality among eight temperate forest tree species alters avian suppression of an assemblage of dietary generalist caterpillars. Plant quality and bird effects varied dramatically among tree species; high-quality plants yielded herbivores of 50% greater mass than those on low-quality plants, and bird effects ranged from near 0% to 97% reductions in caterpillar density. We also find evidence for two mechanisms linking host plant quality to bird effects. If caterpillar density was statistically controlled for, birds had relatively strong effects on the herbivores of low-quality plants, as predicted by the slow-growth/high-mortality hypothesis. At the same time, caterpillar density increased with plant quality, and bird effects were density dependent. Consequently, the net effect of birds was strongest on the herbivores of high-quality plants, a dynamic we call the high-performance/high-mortality hypothesis. Host plant quality thus changes highly generalized herbivore-carnivore interactions by two complementary but opposing mechanisms. These results highlight the interrelatedness of plant-herbivore and herbivore-carnivore interactions and thus the importance of a tritrophic perspective.