Search bioRxiv⌕ Search

Biology subjects

Howie, D.

Publications and source records attributed to Howie, D..

6 recordsLinked to original sources

Unexpected post-release behaviours of reintroduced kakapo

Translocations are commonly used to reduce the risk of extinction of threatened species, and often to reintroduce animals to their former habitats. If extirpation occurred a long time ago, individuals may be placed into novel environments outside of conditions they have previously experienced, which can affect translocation success. To measure success of translocations, particularly those to novel habitats, it is important to monitor post-release spatial behaviour. In 2023, ten critically endangered k[a]k[a]p[o] (Strigops habroptilus) were released to form a new population at the fenced mainland island of Sanctuary Mountain Maungatautari (hereafter Maungatautari) in the North Island of New Zealand, an area from which they were extirpated approximately a century earlier. The spatial behaviour and habitat selection of these k[a]k[a]p[o] was analysed using dynamic space use and step selection functions with temporally dynamic responses applied to GPS logger data recorded over a seven month period. These showed three unexpected results: k[a]k[a]p[o] were highly mobile and used larger areas compared to other sites; there was synchronicity of movement, with most individuals simultaneously moving toward the perimeter fence in spring; and when near the fence k[a]k[a]p[o] selected for areas of pasture and exotic vegetation more than anticipated. While direct comparisons are difficult due to varying data availability, this unexpected spatial behaviour and habitat selection suggests that k[a]k[a]p[o] behavioural responses were different at Maungatautari compared to other sites. This may indicate that k[a]k[a]p[o] released at Maungatautari had a longer exploratory stage than elsewhere; that there were behavioural effects influenced by conspecific density or the availability of novel and exotic vegetation; or that there were specific breeding habitat requirements not met at the site during the study period. These results highlight the importance of high-resolution spatial monitoring to evaluate the success of translocations, particularly those to novel environments.

animal behavior and cognition↗

Conserved allomorphs of MR1 drive specificity of MR1-restricted TCRs

Major histocompatibility complex class-1-related protein (MR1), unlike human leukocyte antigen (HLA) class-1, has until recently been reported to be monomorphic. Tumor cell-specific MR1 restricted T cell receptors (TCRs) have been described, offering potential therapeutic application for cancer treatment. We show that human T cells expressing a TCR derived from an MR1-restricted T cell clone, termed MC.7.G5 (7G5.TCRT), retain MR1-directed cytotoxicity. However, activity is not pan-cancer, as initially reported with the clone MC.7.G5. Recognition is restricted by an allelic variant of MR1 (MR1*04) which is present at approximately 1% of the population at the heterozygote level. The 7G5 TCR is not cancer specific, as 7G5.TCRT and 7G5.TCRT-like TCRs react to both cancer and healthy cells expressing MR1*04 alleles. These data demonstrate that healthy individuals can harbor T cells reactive to an MR1 variant displaying self-ligands expressed in cancer and benign tissues. Targeting MR1 in cancer will require identification of cancer-specific presented ligands, and careful confirmation of cancer specificity of TCRs. MR1*04 may behave as an alloantigen warranting further study.

cancer biology↗

A role of Lck annular lipids in the steady upkeep of active Lck in T cells

Theoretical work suggests that collective spatiotemporal behaviour of integral membrane proteins (IMPs) can be modulated by annular lipids sheathing their hydrophobic moiety. Here, we present evidence for this prediction in a natural membrane by investigating the mechanism that maintains steady amount of active isoform of Lck kinase (LckA) by Lck trans-autophosphorylation offset by the phosphatase CD45. We gauged experimental suitability by quantitation of CD45 and LckA subcellular localisation, LckA generation as a function of Lck and pharmacological perturbation. Steady LckA was challenged by swapping Lck membrane anchor with structurally divergent ones expected to substantially modify Lck annular lipids, such as that of Src or the transmembrane domains of LAT, CD4, palmitoylation-defective CD4 and CD45, respectively. The data showed only small alteration of LckA, except for CD45 hydrophobic anchor that thwarted LckA, due to excessive lateral proximity to CD45. The data are best explained by annular lipids facilitating or penalising IMPs lateral proximity, hence modulating IMPs protein-protein functional interactions. Our findings can contribute to improve the understanding of biomembranes organisation.

cell biology↗

The chaperonin CCT8 controls proteostasis essential for T cell maturation, selection, and function

T cells rely for their development and function on the correct folding and turnover of proteins generated in response to a broad range of molecular cues. In the absence of the eukaryotic type II chaperonin complex, CCT, T cell activation induced changes in the proteome are compromised including the formation of nuclear actin filaments and the formation of a normal cell stress response. Consequently, thymocyte maturation and selection, and T cell homeostatic maintenance and receptor-mediated activation are severely impaired. Additionally, Th2 polarization digresses in the absence of CCT-controlled protein folding resulting paradoxically in continued IFN-{gamma} expression. As a result, CCT-deficient T cells fail to generate an efficient immune protection against helminths as they are unable to sustain a coordinated recruitment of the innate and adaptive immune systems. These findings thus demonstrate that normal T cell biology is critically dependent on CCT-controlled proteostasis and that its absence is incompatible with protective immunity.

immunology↗

GLP-1R is downregulated in beta cells of NOD mice and T1D patients

Glucagon-like peptide 1 (GLP-1) is produced by L cells in the small intestine in response to ingested glucose and increases insulin release from pancreatic beta cells by activation of its cognate receptor (GLP-1R). Stimulation of this receptor also contributes to increased beta cell survival and regeneration. We have found that pancreatic beta cells from Non Obese Diabetic (NOD) mice express significantly lower levels of GLP-1R than C57BL/6 mice, leaving the NOD beta cells with an impaired response to GLP-1 stimulation. The lower expression appears to be caused by accelerated degradation of GLP-1R in the beta cells, a process that can be reversed by inhibiting trafficking to the lysosome. Importantly, our results appear to translate to the human disease since we also observed significantly lower expression of the GLP-1R in pancreatic islets from donors with type 1 diabetes. These results suggest that beta cell physiology may play a role in susceptibility to autoimmune inflammation.

physiology↗

CD4+ T cell fate decisions are stochastic, precede cell division, depend on GITR co-stimulation, and are associated with uropodium development

During an immune response, naive CD4+ T cells proliferate and generate a range of effector, memory and regulatory T cell subsets, but how these processes are co-ordinated remains unclear. A traditional model suggests that memory cells use mitochondrial respiration and are survivors from a pool of previously proliferating and glycolytic, but short-lived effector cells. A more recent model proposes a binary commitment to either a memory or effector cell lineage during a first, asymmetric cell division, with each lineage able to undergo subsequent proliferation and differentiation. We used improved fixation and staining methods with imaging flow cytometry in an optimised in vitro system that indicates a third model. We found that cell fates result from stochastic decisions that depend on GITR co-stimulation and which take place before any cell division. Effector cell commitment is associated with mTORC2 signalling leading to uropodium development, while developing memory cells lose mitochondria, have a nuclear localization of NF{kappa}B and depend on TGF{beta} for their survival. Induced, T helper subsets and foxp3+ regulatory T cells were found in both the effector and memory cell lineages. This in vitro model of T cell differentiation is well suited to testing how manipulation of cytokine, nutrient other components of the microenvironment might be exploited for therapeutic purposes.

immunology↗