Biology subjects

Williams, S. H.

Publications and source records attributed to Williams, S. H..

4 recordsLinked to original sources

bioRxiv2025

Coordinated circulating and tissue-based T cell responses precede xenograft rejection

Despite the life-saving successes of solid organ transplantation, the number of individuals needing organ transplant far exceeds the number of organs available for use each year. Porcine xenotransplantation, or the use of pig organs for transplantation in people, holds substantial promise but xenograft rejection in humans is poorly understood. T cell rejection by the host immune system is a major challenge for human allografts and may limit the longevity of porcine xenografts. To study the xenograft rejection, we evaluated T cell responses and repertoire dynamics across tissues following porcine thymokidney transplantation in a decedent model over 61 days after bilateral native kidney nephrectomy. Despite induction with anti-thymocyte globulin and ongoing immune suppression consisting of rituximab, corticosteroids, calcineurin inhibition, and mycophenolate mofetil, human T cell infiltration of the xenograft was observed and was associated with xenograft dysfunction. Longitudinal analysis of T cell clonotypes in biopsies of thymokidney revealed accumulation of clonal human CD4 and CD8 T cell responses. Moreover, circulating activated T cells, including circulating T follicular helper (cTfh), were xeno-reactive and increased in frequency around rejection events. We confirmed clonal dominance of a single CD8 clonotype - identified as donor-reactive in a mixed lymphocyte reaction - in the circulation leading up to the acute cellular rejection event. Following re-treatment with anti-thymocyte globulin and intensification of corticosteroids, the T cell clonotypes were dramatically diminished in frequency in thymokidney and lymph nodes, though not eliminated. Over time of observation, the T cell clonotypes were shared across multiple compartments, including xenograft, circulation and lymph nodes and formed clonal families with known xeno-reactive clonotypes, suggesting a coordinated immune response against a limited pool of antigenic targets. Together, these data demonstrate T cell repertoire dynamics across tissues in the setting of xenograft rejection and highlight opportunities for early surveillance, prediction and potential intervention. One-sentence summaryAfter pig-to-human kidney xenotransplantation, xenoreactive T cells form clonotypic families across blood, graft, and lymphoid tissues, indicating a coordinated and targeted response.

immunology↗

bioRxiv2023

ANXA11 biomolecular condensates facilitate protein-lipid phase coupling on lysosomal membranes

Phase transitions of cellular proteins and lipids play a key role in governing the organisation and coordination of intracellular biology. The frequent juxtaposition of proteinaceous biomolecular condensates to cellular membranes raises the intriguing prospect that phase transitions in proteins and lipids could be co-regulated. Here we investigate this possibility in the ribonucleoprotein (RNP) granule-ANXA11-lysosome ensemble, where ANXA11 tethers RNP granule condensates to lysosomal membranes to enable their co-trafficking. We show that changes to the protein phase state within this system, driven by the low complexity ANXA11 N-terminus, induce a coupled phase state change in the lipids of the underlying membrane. We identify the ANXA11 interacting proteins ALG2 and CALC as potent regulators of ANXA11-based phase coupling and demonstrate their influence on the nanomechanical properties of the ANXA11-lysosome ensemble and its capacity to engage RNP granules. The phenomenon of protein-lipid phase coupling we observe within this system offers an important template to understand the numerous other examples across the cell whereby biomolecular condensates closely juxtapose cell membranes. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/533832v1_ufig1.gif" ALT="Figure 1"> View larger version (76K): org.highwire.dtl.DTLVardef@16f3e10org.highwire.dtl.DTLVardef@538f39org.highwire.dtl.DTLVardef@1e00d4eorg.highwire.dtl.DTLVardef@89967d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Jaw Kinematics and Tongue Protraction-Retraction during Chewing and Drinking in the Pig

Mastication and drinking are rhythmic and cyclic oral behaviors that require interactions between the tongue, jaw, and a food or liquid bolus, respectively. During mastication, the tongue transports and positions the bolus for breakdown between the teeth. During drinking, the tongue aids in ingestion and then transports the bolus to the oropharynx. The objective of this study is to compare jaw and tongue kinematics during chewing and drinking in pigs. We hypothesize there will be differences in jaw gape cycle dynamics and tongue protraction-retraction between behaviors. Mastication cycles had an extended slow-close phase, reflecting tooth-food-tooth contact, whereas drinking cycles had an extended slow-open phase, corresponding to tongue protrusion into the liquid. Drinking jaw movements were of lower magnitude for all degrees of freedom examined (jaw protraction, yaw, and pitch), and were bilaterally symmetrical with virtually no yaw. The magnitude of tongue protraction-retraction (Tx) was greater during mastication than drinking, but there were minimal differences in the timing of maximum and minimum tongue Tx relative to the jaw gape cycle between behaviors. However, during drinking, the tongue tip is often located outside the oral cavity for the entire cycle, leading to differences in behaviors in the timing of anterior marker maximum tongue Tx. This demonstrates that there is variation in tongue-jaw coordination between behaviors. These results show that jaw and tongue movements vary significantly between mastication and drinking, which hint at differences in the central control of these behaviors. Summary statementDifferences in the magnitude and timing of tongue and jaw movements and the anteroposterior positioning of the tongue during chewing and drinking demonstrate key differences in coordination of these behaviors.

physiology↗

bioRxiv2019

MKPV (aka MuCPV) and related chapparvoviruses are nephro-tropic and encode novel accessory proteins p15 and NS2

Mouse kidney parvovirus (MKPV) is a member of the provisional Chapparvovirus genus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four MKPV transcripts, created by alternative splicing, to a common transcription initiation region, and use mass spectrometry to identify \"p10\" and \"p15\" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and a splicing-dependent putative accessory protein NS2 are conserved in all near-complete tetrapod chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that chapparvoviruses with >60% VP1 amino acid identity to MKPV be classified into a genus dubbed Nephroparvovirus, which is consistent with nomenclature for the genus Erythroparvovirus.

microbiology↗