Biology subjects

Redmond, S. J.

Publications and source records attributed to Redmond, S. J..

7 recordsLinked to original sources

bioRxiv2026

Conserved T cell receptor usage underpins recognition of CD1c presenting a mycobacterial lipid

The mechanism by which T cell receptors (TCR) recognise mycobacterial lipids presented by CD1 family members not well understood. We used CD1c tetramers loaded with the mycobacterial phosphomycoketide (PM) or mannosyl-PM (MPM) to isolate T cells ex vivo in healthy blood donors and in individuals from a tuberculosis (TB)-endemic region of South Africa, with higher frequencies observed in individuals from the TB-endemic region. High throughput analysis of >200 paired CD1c-mycoketide tetramer+ {beta}TCRs identified a conserved TCR motif, encoded by TRBV4-1 or TRBV7-9 variable region genes in greater than half of TCRs sequenced. A cryo-EM structure of a TRBV7-9+ TCR in complex with CD1c-PM demonstrated that the TCR bound to the F side of CD1c, directly contacting the phospholipid antigen and F-portal residues. Analysis of multiple T cell clones interacting with CD1c mutants suggested that this TCR docking mode is representative of the larger TRBV7-9+ T cell population. Collectively, this study provides insight into mycobacterial lipid-antigen recognition by CD1c-restricted T cells. SummaryCao and Soliman et al study CD1c-restricted human T cells that recognize mycobacterial phosphomycoketide lipids, where they are shown to be more frequent in blood a TB-endemic region. The authors describe a strong TCR-{beta} repertoire bias and use cryoEM to provide a high-resolution structure of an archetypal TCR engaging CD1c in complex with a mycobacterial lipid.

immunology↗

bioRxiv2026

Specific targeting of MR1-antigen complexes using nanobodies

T cell receptor mimic (TCRm) antibodies and nanobodies that specifically bind peptide-HLA complexes have great therapeutic potential, as they can target polymorphic HLA on tumour cells furnishing peptides derived from tumour-associated antigens. MR1 is an MHC class-I-like molecule that exhibits limited polymorphism that binds and presents conserved metabolites, such as 5-OP-RU, derived from microbial riboflavin biosynthesis. Whether antibodies targeting such MR1-5-OP-RU complexes can be generated remains unclear. Using yeast display technology and in vitro affinity maturation, a nanobody with high affinity and fine specificity toward MR1-5-OP-RU complex was generated. These nanobodies bind both mouse and human MR1-5-OP-RU and inhibited MAIT cell responses to 5-OP-RU in vitro and in vivo demonstrating therapeutic potential. Moreover, we provide a molecular basis underpinning the fine specificity of these nanobodies, solving the crystal structures of MR1 in complex with either 5-OP-RU or Ac-6-FP. Here, the nanobody co-bound MR1 and 5-OP-RU, akin to a TCRm antibody. Moreover, we engineer bispecific antibodies targeting both MR1-5-OP-RU and CD3, that drive broad T cell killing of bacterially-infected cells as well as tumour cells treated with 5-OP-RU, thereby providing proof-of-principle for targeting the MR1 molecule with with TCRm-based nanobodies. One Sentence SummaryWe report the development of a nanobody targeting MR1-5-OP-RU complex and demonstrate its utility to modulate MAIT cells responses, and as a bispecific engager.

immunology↗

bioRxiv2023

Role of finger movement kinematics in friction perception at initial contact with smooth surfaces

When manipulating objects, humans adjust grip force to friction remarkably quickly: it may take just 100 ms to see adjustment to friction at the skin-object interface. While the motor commands adapt, subjects become aware of slipperiness of touched surfaces. In this study, we explore the sensory processes underlying such friction perception when no intentional exploratory sliding movements are present. Previously, we have demonstrated that humans cannot perceive frictional differences when surfaces are brought in contact with an immobilized finger (Khamis et al., 2021b) unless there is a submillimeter lateral displacement (Afzal et al., 2022), or subjects made the movement themselves (Willemet et al., 2021). In the current study, subjects actively interacted with a device that can modulate friction using ultrasound, without an exploratory sliding movement, as they would when gripping an object to lift it. Using a two-alternative forced-choice paradigm, subjects had to indicate which of two surfaces felt more slippery. Subjects could correctly identify the more slippery surface in 87 {+/-} 8% of cases (mean{+/-}SD; n=12). Biomechanical analysis of finger pad skin contacting a flat smooth surface indicated that natural movement kinematics (e.g., tangential movement jitter and physiological tremor) may enhance perception of frictional effects. To test whether this is the case, in a second experiment a hand support was introduced to limit fingertip movement deviation from a straight path. Subject performance significantly decreased (66 {+/-} 12% correct, mean{+/-}SD; n=12), indicating that friction perception at the initial contact is enhanced or enabled by natural movement kinematics. Significance statementSensing surface friction is crucial for automatic grip force control to avoid dropping objects. A slipping handhold can lead to loss of balance and falling. In many instances, the required grip force may exceed hands physical ability or an objects breakage point, therefore cognitive selection of a safe and achievable action plan based on friction perception is critical. Little is known about how our awareness of surface slipperiness is obtained under such circumstances without exploratory movement. The current study demonstrates that natural movement kinematics inducing submillimeter lateral movements play a central enabling role, demonstrating interdependence between the motor system and sensory mechanisms. These findings broaden our fundamental understanding of sensorimotor control and could inform the development of advanced sensor technologies.

neuroscience↗

bioRxiv2023

Open-source instrumented object to study dexterous object manipulation

Humans use tactile feedback to perform skillful manipulation. When tactile sensory feedback is unavailable, for instance, if the fingers are anesthetized, dexterity is severely impaired. Imaging the deformation of the finger pad skin when in contact with a transparent plate provides information about the tactile feedback received by the central nervous system. Indeed, skin deformations are transduced into neural signals by the mechanoreceptors of the finger pad skin. Understanding how this feedback is used for active object manipulation would improve our understanding of human dexterity. In this paper, we present a new device for imaging the skin of the finger pad of one finger during manipulation performed with a precision grip. The devices weight (300 g) makes it easy to use during unconstrained dexterous manipulation. Using this device, we reproduced the experiment performed in Delhaye et al. 2021a. We extracted the strains aligned with the objects movement, i.e., the vertical strains in the ulnar and radial parts of the fingerpad, to see how correlated they were with the grip force (GF) adaptation. Interestingly, parts of our results differed from those in Delhaye et al. 2021a due to weight and inertia differences between the devices, with average GF across participants differing significantly. Our results highlight a large variability in the behavior of the skin across participants, with generally low correlations between strain and GF adjustments, suggesting that skin deformations are not the primary driver of GF adaptation in this manipulation scenario. Significance statementIn this paper, we introduce a new device weighing 300 g and capable of imaging the skin of the finger pad of one finger during manipulation performed with a precision grip. This object is also capable of recording the forces and accelerations applied to the object. We reproduced the experiment performed in Delhaye et al. 2021a using this device. We extracted the strains aligned with the objects movement to analyze how correlated these strains were with GF adaptation. The behavior of the skin across participants presented a large variability, and we observed low correlations between strain and GF adjustments in most participants. Our results suggest that skin deformations are not the primary driver of GF adaptation in this manipulation scenario.

neuroscience↗

bioRxiv2023

Vgamma9Vdelta2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

Butyrophilin (BTN) molecules are emerging as key regulators of T cell immunity, however, how they trigger cell-mediated responses is poorly understood. Here, the crystal structure of a gamma-delta T cell receptor ({gamma}{delta}TCR) in complex with BTN member 2A1 (BTN2A1) revealed that BTN2A1 engages the side of the {gamma}{delta}TCR, leaving the apical TCR surface bioavailable. We reveal that BTN3A1 is a second {gamma}{delta}TCR ligand, that co-engages {gamma}{delta}TCR via binding to this accessible apical surface. BTN2A1 and BTN3A1 also directly interact with each other in cis, and structural analysis revealed formation of W-shaped heteromeric multimers. This BTN2A1-BTN3A1 interaction involved the same epitopes that BTN2A1 and BTN3A1 each use to engage {gamma}{delta}TCR; indeed, either forced separation or locking together of BTN2A1 and BTN3A1 resulted in enhanced or abrogated {gamma}{delta}TCR interaction, respectively. Our findings reveal a new paradigm in immune activation, whereby {gamma}{delta}TCRs recognize dual epitopes on BTN2A1 and BTN3A1 complexes.

immunology↗

bioRxiv2022

Biomechanics of Finger Pad Response under Torsion

Surface skin deformation of the finger pad during partial slippage at finger-object interfaces elicits tactile feedback. During object manipulation, torque is often present, which can cause partial slippage. Until now, studies of surface skin deformation have used stimuli sliding on rectilinear tangential trajectories. Here we studied surface skin dynamics under torsion. A custom robotic platform stimulated the finger pad with a flat transparent surface, controlling the normal forces and rotation speeds applied while monitoring the contact interface using optical imaging. We observed the characteristic pattern by which partial slips develop, starting at the periphery of the contact and propagating towards its centre, and the resulting surface strains. The 20-fold range of normal forces and angular velocities used highlights the effect of those parameters on the resulting torque and skin strains. While normal force increases the contact area, generated torque, strains, and twist angle required to reach full slip, angular velocity increases loss of contact at the periphery and strain rates (although not total strains). We also discuss the surprisingly large inter-individual variability in skin biomechanics, notably observed in the twist angle the stimulus needed to rotate before reaching full slip.

neuroscience↗

bioRxiv2021

CD36 family members are TCR-independent ligands for CD1 antigen-presentingmolecules

CD1c presents lipid-based antigens to CD1c-restricted T cells which are thought to be a major component of the human T cell pool. The study of CD1c-restricted T cells, however, is hampered by the presence of an abundantly expressed CD1c-binding partner on blood cells distinct to the T cell receptor (TCR), confounding analysis of TCR-mediated CD1c tetramer staining. Here, we identify the CD36 family (CD36, CD36-L1 and CD36-L2) as novel ligands for CD1c, CD1b and CD1d proteins, and show that CD36 is the receptor responsible for non-TCR-mediated CD1c tetramer staining of blood cells. Moreover, CD36-blockade enables tetramer-based identification of CD1c-restricted T cells and clarifies identification of CD1b- and CD1d-restricted T cells. We use this technique to characterise CD1c-restricted T cells ex vivo and show diverse phenotypic features, TCR repertoire and antigen-specific subsets. Accordingly, this work will enable further studies into the biology of CD1 and human CD1-restricted T cells. One Sentence SummaryCD1 molecules bind CD36 family members and blockade of this interaction facilitates the study of CD1-restricted T cells.

immunology↗