Jack of all trades, master of all: a positive association between habitat niche breadth and foraging performance in pit-building antlion larvae

Species utilizing a wide range of resources are intuitively expected to be less efficient in exploiting each resource type compared to species which have developed an optimal phenotype for utilizing only one or a few resources. We report here the results of an empirical study whose aim was to test for a negative association between habitat niche breadth and foraging performance. As a model system to address this question, we used two highly abundant species of pit-building antlions varying in their habitat niche breadth: the habitat generalist Myrmeleon hyalinus, which inhabits a variety of soil types but occurs mainly in sandy soils, and the habitat specialist Cueta lineosa, which is restricted to light soils such as loess. Both species were able to discriminate between the two soils, with each showing a distinct and higher preference to the soil type providing higher prey capture success and characterizing its primary habitat-of-origin. As expected, only small differences in the foraging performances of the habitat generalist were evident between the two soils, while the performance of the habitat specialist was markedly reduced in the alternative sandy soil. Remarkably, in both soil types, the habitat generalist constructed pits and responded to prey faster than the habitat specialist, at least under the temperature range of this study. Furthermore, prey capture success of the habitat generalist was higher than that of the habitat specialist irrespective of the soil type or prey ant species encountered, implying a positive association between habitat niche-breadth and foraging performance. Alternatively, C. lineosa specialization to light soils does not necessarily confer upon its superiority in utilizing such habitats. We thus suggest that habitat specialization in C. lineosa is either an evolutionary dead-end, or, more likely, that this species' superiority in light soils can only be evident when considering additional niche axes.     

Genome sequence of Aeromonas hydrophila ATCC 7966T: jack of all trades

The complete genome of Aeromonas hydrophila ATCC 7966(T) was sequenced. Aeromonas, a ubiquitous waterborne bacterium, has been placed by the Environmental Protection Agency on the Contaminant Candidate List because of its potential to cause human disease. The 4.7-Mb genome of this emerging pathogen shows a physiologically adroit organism with broad metabolic capabilities and considerable virulence potential. A large array of virulence genes, including some identified in clinical isolates of Aeromonas spp. or Vibrio spp., may confer upon this organism the ability to infect a wide range of hosts. However, two recognized virulence markers, a type III secretion system and a lateral flagellum, that are reported in other A. hydrophila strains are not identified in the sequenced isolate, ATCC 7966(T). Given the ubiquity and free-living lifestyle of this organism, there is relatively little evidence of fluidity in terms of mobile elements in the genome of this particular strain. Notable aspects of the metabolic repertoire of A. hydrophila include dissimilatory sulfate reduction and resistance mechanisms (such as thiopurine reductase, arsenate reductase, and phosphonate degradation enzymes) against toxic compounds encountered in polluted waters. These enzymes may have bioremediative as well as industrial potential. Thus, the A. hydrophila genome sequence provides valuable insights into its ability to flourish in both aquatic and host environments.     

Murine models define the role of TGF-beta as a master regulator of immune cell function

Many members of transforming growth factor-beta (TGF-beta) superfamily, including not only TGF-beta, but also the activins, and bone morphogenetic proteins (BMPs), have been demonstrated to affect the development and function of immune cells. From the proliferation and differentiation of pluripotent stem cells, to the activation and migration of mature lymphoid and myeloid lineages, the TGF-betas have been recognized for their ability to modulate the manner in which such cells respond to stimuli in their environment. Recent studies involving disruption of this pathway in genetically engineered mice now emphasize the importance of this activity and validate functional models predicted by in vitro studies. Phenotypic differences between mice harboring mutations in the TGF-beta1 ligand and the TGF-beta receptor-activated signaling intermediate Smad3 are presented and serve to highlight the valuable role of these in vivo genetic tests of function.     

TGF-beta as a T cell regulator in colitis and colon cancer

TGF-beta is a pleiotropic cytokine with powerful immunosuppressive functions. Mice deficient for TGF-beta1 show a dramatic phenotype with severe multiorgan inflammation and die shortly after birth. Recent investigations have highlighted the role of TGF-beta in suppression of T cell mediated autoimmune inflammation and anti-tumor immunity. In addition to its direct anti-inflammatory effects on T cells, TGF-beta has been implicated as central regulator of regulatory T cells. TGF-beta not only mediates the suppression of effector T cells by Tregs, recent evidence also reveals a role for TGF-beta along with TCR stimulation in the peripheral induction of regulatory T cells from na?ve CD4+CD25- cells.     

Transforming growth factor-beta (TGF-beta)-resistant helper T lymphocyte clones show a concomitant loss of all three types of TGF-beta receptors.

Three ovalbumin-specific T helper cell lines (OVA-7T cells) that differ in their susceptibility to the immunosuppressive effects of transforming growth factor-beta (TGF-beta) were cloned. The frequency of TGF-beta-resistant OVA-7T cell clones correlated with the decline of TGF-beta sensitivity in the original OVA-7T parental cell lines. In TGF-beta-resistant OVA-7T cell clones, TGF-beta inhibited neither the growth of the T cells nor their secretion of granulocyte macrophage CSF. TGF-beta suppressed the expression of c-myc mRNA in OVA-7T-responder but not in OVA-7T-nonresponder cells. TGF-beta resistance was found to be due to a loss of TGF-beta high-affinity binding sites, with an absence of expression of the distinct 54-, 70-, 110-, and 250-kDa surface proteins that bind TGF-beta on TGF-beta-susceptible T cells. Loss of TGF-beta R may enable T cells to escape the negative feedback control provided by TGF-beta secreted from activated T cells during an immune response.     

Characterization of a monoclonal antibody which detects all murine alpha beta T cell receptors

Research on the specificities, functions, and maturation of T cells would be greatly aided by a collection of monoclonal antibodies which distinguishes different types of TCR. With this end in mind hamsters were immunized and tested for production of pan-reactive anti-mouse alpha beta TCR antibodies. In this report we describe the properties and uses of a mAb, H57-597, produced from one of these animals. The mAb reacts with surface receptors on all alpha beta TCR-bearing cells and does not react with receptors on gamma delta+ T cells. In an immobilized form, this antibody can directly activate T cells bearing alpha beta TCR. It can be used in immunoprecipitation reactions to precipitate receptor from the appropriate cell types. In combination with anti-CD3, the antibody can be used in cytofluorographic analyses to measure numbers of CD3+, alpha beta+, and CD3+, gamma delta+ cells in the thymus and periphery.     

Rop GTPase: a master switch of cell polarity development in plants

Cell polarity is fundamentally important to plant growth and development, yet the mechanism governing its development is understood poorly. Several studies have revealed a role for Rop GTPases in pollen polar tip growth. Rop is also localized to the future site of root hair development and the tip of root hairs, and expression of constitutively active Rop mutants impacts on the morphogenesis of tip-growing root hairs as well as on non-tip-growing cells. These findings highlight the importance of Rop as a common switch in cell polarity control in plants.     

TGF-beta 1 regulates antigen-specific CD4+ T cell responses in the periphery

T cell expansion typically is due to cognate interactions with specific Ag, although T cells can be experimentally activated through bystander mechanisms not involving specific Ag. TGF-beta1 knockout mice exhibit a striking expansion of CD4+ T cells in the liver by 11 days of age, accompanied by CD4+T cell-dependent necroinflammatory liver disease. To examine whether hepatic CD4+T cell expansion in TGF-beta1(-/-) mice is due to cognate TCR-peptide interactions, we used spectratype analysis to examine the diversity in TCR Vbeta repertoires in peripheral CD4+T cells. We reasoned that Ag-nonspecific T cell responses would yield spectratype profiles similar to those derived from control polyclonal T cell populations, whereas Ag-specific T cell responses would yield perturbed spectratype profiles. Spleen and liver CD4+T cells from 11-day-old TGF-beta1(-/-) mice characteristically exhibited highly perturbed nonpolyclonal distributions of TCR Vbeta CDR3 lengths, indicative of Ag-driven T cell responses. We quantitatively assessed spectratype perturbation to derive a spectratype complexity score. Spectratype complexity scores were considerably higher for TGF-beta1(-/-) CD4+ T cells than for TGF-beta1(+/-) CD4+T cells. TCR repertoire perturbations were apparent as early as postnatal day 3 and preceded both hepatic T cell expansion and liver damage. By contrast, TGF-beta1(-/-) CD4+ single-positive thymocytes from 11-day-old mice exhibited normal unbiased spectratype profiles. These results indicate that CD4+ T cells in TGF-beta1(-/-) mice are activated by and respond to self-Ags present in the periphery, and define a key role for TGF-beta1 in the peripheral regulation of Ag-specific CD4+ T cell responses.     

In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1

Down-regulation of CD4+CD25+ regulatory T (Treg) cell function might be beneficial to enhance the immunogenicity of viral and tumor vaccines or to induce breakdown of immunotolerance. Although the mechanism of suppression used by Treg cells remains controversial, it has been postulated that TGF-beta1 mediates their immunosuppressive activity. In this study, we show that P17, a short synthetic peptide that inhibits TGF-beta1 and TGF-beta2 developed in our laboratory, is able to inhibit Treg activity in vitro and in vivo. In vitro studies demonstrate that P17 inhibits murine and human Treg-induced unresponsiveness of effector T cells to anti-CD3 stimulation, in an MLR or to a specific Ag. Moreover, administration of P17 to mice immunized with peptide vaccines containing tumor or viral Ags enhanced anti-vaccine immune responses and improved protective immunogenicity against tumor growth or viral infection or replication. When CD4+ T cells purified from OT-II transgenic mice were transferred into C57BL/6 mice bearing s.c. EG.7-OVA tumors, administration of P17 improved their proliferation, reduced the number of CD4+Foxp3+ T cells, and inhibited tumor growth. Also, P17 prevented development of immunotolerance induced by oral administration of OVA by genetically modified Lactococcus lactis in DO11.10 transgenic mice sensitized by s.c. injection of OVA. These findings demonstrate that peptide inhibitors of TGF-beta may be a valuable tool to enhance vaccination efficacy and to break tolerance against pathogens or tumor Ags.     

Regulation of TGF-beta response during T cell activation is modulated by IL-10.

TGF-beta1 is an important pleiotropic cytokine that has been described to have both stimulatory and inhibitory effects on cell growth and differentiation. For several cell types, the effect of TGF-beta1 was found to correlate with the differentiation stage of the cells and the presence of other cytokines. In this report, we address the influence of TGF-beta1 on CD4(+) T cell activation by evaluating the effect of TGF-beta1 on the proliferative and cytokine responses of purified resting and activated human or mouse CD4(+) T cells. TGF-beta1 inhibits proliferation and cytokine secretion on resting CD4(+) T cells but has no inhibitory effect on activated T cells. Moreover, TGF-beta1 unresponsiveness of activated T cells was correlated with a down-regulation in the expression of the TGF-beta receptor type II. Interestingly, IL-10 addition enhances TGF-beta receptor type II expression and restores TGF-beta responsiveness on activated T cells. These results indicated that TGF-beta responsiveness is sequentially regulated on T cells by the modulation of the of TGF-beta receptor type II chain expression. Moreover, we have identified a novel regulatory role of IL-10 on TGF-beta-dependent T cell growth that can explain the control of T cell activation on chronic vs acute inflammatory sites.     

Pathologic concentrations of interleukin 6 inhibit T cell responses via induction of activation of TGF-beta

Interleukin 6 levels are increased in a variety of clinical conditions including bacterial and viral infections, HIV infection, autoimmune diseases, certain neoplasias, and traumatic injury. In general, all these conditions are characterized by suppression of one or more manifestations of the immune response. Concentrations of IL 6 comparable to those found in the sera of immunosuppressed, thermally injured patients selectively inhibit T cell proliferative responses. This suppression is independent of IL 2-mediated responses, is dependent on macrophage activity, and is reversed by antisera specific for transforming growth factor-beta (TGF-beta).     

TGF-beta1: immunosuppressant and viability factor for T lymphocytes

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine with multiple roles in the immune system. To date, it has been difficult to develop a comprehensive picture of the effect of TGF-beta on T lymphocytes, because TGF-beta not only acts directly on T lymphocytes, but also acts indirectly by regulating the function of antigen-presenting cells. In early studies, it was mostly the inhibitory function of TGF-beta that was demonstrated; recently, however TGF-beta was recognized as an antiapoptotic survival factor for T lymphocytes. The outcome of the TGF-beta effect on T lymphocytes was shown to strongly depend on their stage of differentiation and on the cytokine milieu. TGF-beta cannot be classified as a classical Th1 or Th2 cytokine. However, recently the existence of the TGF-beta-producing Th3 subset was described which might play an important regulatory role during an immune response. A better understanding of the molecular mechanism of how TGF-beta inhibits or stimulates T lymphocytes will help to predict the complex functions of this cytokine.     

TGF-beta regulates airway responses via T cells

Allergic asthma is characterized by airway hyperreactivity, inflammation, and a Th2-type cytokine profile favoring IgE production. Beneficial effects of TGF-beta and conflicting results regarding the role of Th1 cytokines have been reported from murine asthma models. In this study, we examined the T cell as a target cell of TGF-beta-mediated immune regulation in a mouse model of asthma. We demonstrate that impairment of TGF-beta signaling in T cells of transgenic mice expressing a dominant-negative TGF-beta type II receptor leads to a decrease in airway reactivity in a non-Ag-dependent model. Increased serum levels of IFN-gamma can be detected in these animals. In contrast, after injection of OVA adsorbed to alum and challenge with OVA aerosol, transgenic animals show an increased airway reactivity and inflammation compared with those of wild-type animals. IL-13 levels in bronchoalveolar lavage fluid and serum as well as the number of inducible NO synthase-expressing cells in lung infiltrates were increased in transgenic animals. These results demonstrate an important role for TGF-beta signaling in T cells in the regulation of airway responses and suggest that the beneficial effects observed for TGF-beta in airway hyperreactivity and inflammation may be due to its regulatory effects on T cells.     

Distinct effects of TGF-beta 1 on CD4+ and CD8+ T cell survival, division, and IL-2 production: a role for T cell intrinsic Smad3

TGF-beta1 is critical for maintaining T cell homeostasis. Smad3 has been implicated in this regulatory process, yet the cellular targets and molecular details remain poorly understood. In this study, we report that TGF-beta1 impairs the entry of CD4+ and CD8+ T cells into the cell cycle as well as their progression through subsequent rounds of division, and show that Smad3 is essential for TGF-beta1 to inhibit TCR-induced division of only CD4+ and not CD8+ T cells. Both CD8+ and CD4+ T cells from Smad3-/- mice were refractory to TGF-beta1-induced inhibition of IL-2 production, thus demonstrating that not all CD8+ T cell responses to TGF-beta1 are Smad3 independent. These TGF-beta1 effects were all T cell intrinsic, as they were reproduced in purified CD4+ and CD8+ T cells. Finally, we found that Smad3 was critical for the survival of CD8+, but not CD4+ T cells following activation ex vivo. The TCR-induced death of Smad3-/- CD8+ T cells was not dependent upon TNF-alpha production. Exogenous TGF-beta1 partially rescued the CD8+ T cells by signaling through a Smad3-independent pathway. TGF-beta1 also enhanced survival of TCR-stimulated CD4+CD44high T cells in a Smad3-independent manner. Collectively, these findings firmly establish for the first time that TGF-beta1 discriminately regulates CD4+ and CD8+ T cell expansion by signaling through distinct intracellular pathways.     

Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta.

Induction and maintenance of Ag-specific tolerance are pivotal for immune homeostasis, prevention of autoimmune disorders, and the goal of transplantation. Recent studies suggest that certain cytokines, notably IL-10 and TGF-beta, may play a role in down-regulating immune functions. To further examine the role of cytokines in Ag-specific hyporesponsiveness, murine CD4+ T cells were exposed ex vivo to alloantigen-bearing stimulators in the presence of exogenous IL-10 and/or TGF-beta. Primary but not secondary alloantigen proliferative responses were inhibited by IL-10 alone. However, the combined addition of IL-10 + TGF-beta markedly induced alloantigen hyporesponsiveness in both primary and secondary MLR cultures. Alloantigen-specific hyporesponsiveness was observed also under conditions in which nominal Ag responses were intact. In adoptive transfer experiments, IL-10 + TGF-beta-treated CD4+ T cells, but not T cells treated with either cytokine alone, were markedly impaired in inducing graft-vs-host disease alloresponses to MHC class II disparate recipients. These data provide the first formal evidence that IL-10 and TGF-beta have at least an additive effect in inducing alloantigen-specific tolerance, and that in vitro cytokines can be exploited to suppress CD4+ T cell-mediated Ag-specific responses in vivo.