Spider Origami: Folding Principle of Jumping Spider Leg Joints for Bioinspired Fluidic Actuators.

Jumping spiders (Phidippus regius) are known for their ability to traverse various terrains and have targeted jumps within the fraction of a second to catch flying preys. Different from humans and insects, spiders use muscles to flex their legs, and hydraulic actuation for extension. By pressurizing their inner body fluid, they can achieve fast leg extensions for running and jumping. Here, the working principle of the articular membrane covering the spider leg joint pit is investigated. This membrane is highly involved in walking, grasping, and jumping motions. Hardness and stiffness of the articular membrane is studied using nanoindentation tests and preparation methods for scanning electron microscopy and histology are developed to give detailed information about the inner and outer structure of the leg joint and its membrane. Inspired by the stroller umbrella-like folding mechanism of the articular membrane, a robust thermoplastic polyurethane-based rotary semifluidic actuator is demonstrated, which shows increased durability, achieves working angles over 120°, produces high torques which allows lifts over 100 times of its own weight and jumping abilities. The developed actuator can be used for future grasping tasks, safe human-robot interactions and multilocomotion ground robot applications, and it can shed light into spider locomotion-related questions.

A Th17-like developmental process leads to CD8(+) Tc17 cells with reduced cytotoxic activity.

Activation of naive CD8(+) T cells with antigen in the absence of skewing cytokines triggers their differentiation into effector CTL, which induces death of target cells. We show that CD8(+) T cells activated in the presence of the cytokines IL-6 or IL-21 plus TGF-beta similar to CD4(+) T cells, develop into IL-17-producing (Tc17) cells. These cells display greatly suppressed cytotoxic function along with low levels of the CTL markers: T-box transcription factor Eomesodermin, granzyme B and IFN-gamma. Instead, these cells express hallmark molecules of Th17 program including retinoic acid receptor-related orphan receptor (ROR)gammat, RORalpha, IL-21 and IL-23R. The expression of the type 17 master regulator RORgammat is causally linked to Tc17 generation, because its overexpression stimulates production of IL-17 in the presence of IL-6 or IL-21. Both, upregulation of the type 17 program as well as suppression of CTL differentiation are STAT3 dependent. Furthermore, Tc17 cells producing IL-17 but not granzyme B are also detectable in EAE, a mouse model for multiple sclerosis. Our data point to the existence of mutually exclusive CTL and Tc17 developmental pathways in vitro and in vivo.

CD28 and IL-4: two heavyweights controlling the balance between immunity and inflammation.

The costimulatory receptor CD28 and IL-4Ralpha containing cytokine receptors play key roles in controlling the size and quality of pathogen-specific immune responses. Thus, CD28-mediated costimulation is needed for effective primary T-cell expansion and for the generation and activation of regulatory T-cells (Treg cells), which protect from immunopathology. Similarly, IL-4Ralpha signals are required for alternative activation of macrophages, which counteract inflammation by type 1 responses. Furthermore,immune modulation by CD28 and IL-4 is interconnected through the promotion of IL-4 producing T-helper 2 cells by CD28 signals. Using conditionally IL-4Ralpha and CD28 deleting mice, as well as monoclonal antibodies, which block or stimulate CD28, or mAb that deplete Treg cells, we have studied the roles of CD28 and IL-4Ralpha in experimental mouse models of virus (influenza), intracellular bacteria (L. monocytogenes, M. tuberculosis), and parasite infections (T. congolense, L. major). We observed that in some, but not all settings, Treg cells and type 2 immune deviation, including activation of alternative macrophages can be manipulated to protect the host either from infection or from immunopathology with an overall beneficial outcome. Furthermore, we provide direct evidence that secondary CD8 T-cell responses to i.c. bacteria are dependent on CD28-mediated costimulation.

Treatment and prevention of experimental autoimmune neuritis with superagonistic CD28-specific monoclonal antibodies.

Two distinct CD28-specific mAb were used in treatment of active or adoptive transfer (AT)-experimental autoimmune neuritis (EAN): "superagonistic" JJ316 activates T cells without T cell receptor (TCR) occupancy, and conventional JJ319 activates T cells only in the presence of TCR-stimulation. Treatment with JJ316 during induction phase of active and adoptive-transfer experimental autoimmune encephalomyelitis (AT-EAN) dramatically reduced disease severity and improved nerve function as revealed by electrophysiology. JJ316 given 1 week before immunization had a preventive effect. By immunohistology, JJ316 markedly reduced TC infiltration of the sciatic nerve in active and AT-EAN. JJ319 was less effective. Ex vivo, JJ316 therapy reduced P2-specific proliferation and interferon-gamma (IFN-gamma) production of lymph node cells. We demonstrate preventive and therapeutic effects of a "superagonistic" mAb-mediated, TCR-independent CD28 stimulation in EAN, possibly with implications for therapy of autoimmune-inflammatory disorders.

Rapid regulatory T-cell response prevents cytokine storm in CD28 superagonist treated mice.

Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T-cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic release of proinflammatory cytokines, indicating that in rodents, Treg cells effectively suppress the inflammatory response. Since the human volunteers of the TGN1412 study were not protected by this mechanism, we also tested whether corticosteroid prophylaxis would be compatible with CD28SA induced Treg activation. We show that neither the expansion nor the functional activation of Treg cells is affected by high-dose dexamethasone sufficient to control systemic cytokine release. Our findings warn that preclinical testing of activating biologicals in rodents may miss cytokine release syndromes due to the rapid and efficacious response of the rodent Treg compartment, and suggest that polyclonal Treg activation is feasible in the presence of antiphlogistic corticosteroid prophylaxis.

Rapid recovery from T lymphopenia by CD28 superagonist therapy.

Slow recovery of T-cell numbers and function contributes to the high incidence of life-threatening infections after cytotoxic cancer therapies. We have tested the therapeutic potential of a novel class of superagonistic CD28-specific antibodies that induce polyclonal T-cell proliferation without T-cell receptor engagement in an experimental rat model of T lymphopenia. We show that in lethally irradiated, bone marrow-reconstituted hosts, CD28 superagonist is able to dramatically accelerate repopulation by a small inoculum of mature, allotype-marked T cells. CD28-driven recovery of CD4 cells was superior to that of CD8 T cells. CD28 superagonist- expanded CD4 T cells had maintained repertoire diversity and were functional both in vitro and in vivo, suggesting that treatment with a human CD28-specific superagonist will protect T-lymphopenic patients from opportunistic infections.