Biology subjects

Johnson, S. C.

Publications and source records attributed to Johnson, S. C..

At least 19 recordsLinked to original sources

bioRxiv2026

Hypoxia versus immune depletion - immune profiling and treatment cessation provide mechanistic insights and considerations for translation in Leigh syndrome

Genetic mitochondrial diseases (GMDs) are major challenges to human health accounting for a significant fraction of heritable neurologic diseases, myopathies, and inborn errors of metabolism. Leigh syndrome (LS) is the most common clinical presentation of GMD in pediatric patients. LS is a severe and complex disease for which effective clinical therapies are currently lacking. Preclinical therapies identified in the Ndufs4(-/-) mouse model of LS include immune-targeting interventions and chronic mild hypoxia (11% oxygen). Immune-targeting interventions include rapamycin and high-dose pexidartinib, the latter appearing to fully suppress disease. The mechanisms underlying the benefits of hypoxia remain unclear, and the relationship between hypoxia and immune interventions have not been assessed. Here, we report the immune profile of brainstem of the Ndufs4(-/-) mouse model prior to and after disease onset and the impact of pexidartinib treatment. We provide evidence that macrophages/monocytes drive pathology, consistent with recent genetic studies. We additionally find that pre-disease onset animals lack signs of inflammation, and that the elimination of leukocytes fully suppresses the molecular signature of disease. Finally, using distinct post-developmental periods of treatment, we find pexidartinib and rapamycin provide benefits which persist long beyond treatment cessation, while cessation of hypoxia results in rapid disease onset and an acceleration of disease progression. These findings are consistent with hypoxia acting upstream of immune cell activation and have major implications for the therapeutic translation of both hypoxia and immune targeting interventions. Our findings establish hypoxia-cessation as a novel method for synchronizing inflammatory disease onset in the Ndufs4(-/-) model which will be useful in future mechanistic studies.

pathology↗

bioRxiv2026

Predicting Autopsy-Confirmed Neuropathology across Clinical, Neuroimaging, and CSF Biomarkers using Machine Learning

Accurate in vivo prediction of neuropathology is critical for advancing diagnosis and treatment of Alzheimers disease and related dementias (ADRDs). As many individuals with ADRDs have mixed pathologies ({beta}-amyloid, pathologic tau, cerebrovascular disease, vascular brain injury, pathologic TDP-43, hippocampal sclerosis, Lewy bodies), there is interest in determining how accurately we can infer these pathologic changes from clinical data, biofluid assays (e.g., CSF), and neuroimaging. Here we evaluated automated machine learning models trained on data curated by the AD Sequencing Project Phenotype Harmonization Consortium (N=7,894 individuals), to predict 26 autopsy-confirmed neuropathological outcomes. Predictors included in vivo clinical and cognitive composite scores, brain measures from 3D structural MRI and diffusion tensor imaging, image-derived measures of white matter hyperintensities (WMH), and CSF biomarkers. Predictive models were trained using ensemble learning with stratified cross-validation. We assessed performance using Spearmans rank correlation and Matthews correlation coefficient, to accommodate co-occurring pathologic changes. The added value of neuroimaging and CSF versus clinical features alone was quantified. Braak stage was among the most consistently predicted outcomes. CSF biomarkers best predicted {beta}-amyloid and tau pathology, but diffusion MRI metrics best captured vascular brain injury and white matter injury, and outperformed clinical and cognitive measures and anatomical MRI in predicting Lewy body disease. Anatomical measures from structural MRI outperformed standard clinical assessments in assessing neurodegeneration and hippocampal sclerosis, and WMH complemented cognitive measures in predicting TDP-43 pathology. These results establish a baseline for comparing modalities for inferring neuropathology.

neuroscience↗

bioRxiv2026

MyD88 deficiency modestly attenuates disease in a Leigh syndrome mouse model while enrofloxacin accelerates disease

Primary genetic mitochondrial diseases (GMDs) are a clinically and genetically diverse group of diseases estimated to impact over 1 in 4,000 individuals. Leigh syndrome (LS) is the most common pediatric presentation of GMD. LS typically presents within the first years of life and is a severe progressive multi-system disorder. Symmetric progressive inflammatory brain lesions are a defining feature of the disease. Patients can also present with seizures, metabolic dysfunction, muscle weakness, and other symptoms. No effective clinical treatments currently exist. Recent data from the Ndufs4(-/-) mouse model shows that peripheral macrophages contribute to brain lesions in LS, that disease is causally driven by innate immune populations, and that depletion of innate immune cells prevents LS disease. However, the precise mechanisms underlying immune activation remain unknown. Certain mitochondrial macromolecules retain bacterial signatures and can act as potent agonists for innate immune pathways. For example, cytoplasmic mitochondrial RNA and mitochondrial DNA are detected by Toll-like receptors (TLRs) 7 and 9, respectively, at the endosome. Accordingly, these are considered strong candidates for mediating innate immune activation in LS. Here, we generated TLR signaling deficient Ndufs4(-/-)/MyD88(-/-) animals to assess whether TLR signaling plays a role in disease onset or progression in LS. Loss of MyD88 in Ndufs4(-/-) animals statistically significantly increased survival and delayed the onset of some symptoms, but the benefits were modest compared to CSF1R inhibition from prior work. We conclude that Myd88-mediated immune signaling is not a primary driver of LS. Notably, prophylactic enrofloxacin treatment, which was necessary for production of innate immune deficient MyD88(-/-) animals, modestly decreased survival and accelerated disease. The impact of enrofloxacin and similar drugs in the context of mitochondrial disease warrants further investigation.

neuroscience↗

bioRxiv2025

Evaluation of Deep Learning Algorithms to Predict Multiple Dementia-Related Neuropathologies from Brain MRI, Clinical and Genetic Data

Alzheimers disease and related dementias (ADRD) involve overlapping neurodegenerative and vascular pathologies--such as amyloid-{beta} (A{beta}), tau, cerebral amyloid angiopathy (CAA), TDP-43, and alpha-synuclein--that complicate diagnosis and treatment. While PET and CSF biomarkers are useful for detecting A{beta} and tau, they are invasive, expensive, and not widely available. In contrast, magnetic resonance imaging (MRI) is non-invasive and widely accessible, offering an opportunity for pathology prediction when combined with deep learning. Most prior studies have focused on single-pathology detection, but there remains a need for models that can jointly predict multiple co-occurring pathologies. In this work, we evaluate deep learning models that integrate structural MRI with demographic, clinical, and genetic data to classify six autopsy-confirmed neuropathologies: A{beta}, tau, CAA, TDP-43, hippocampal sclerosis, and dementia with Lewy bodies. We compare our hybrid deep learning model to AutoGluon, an automated machine learning framework. Our findings support the potential of multimodal AI to enable non-invasive, comprehensive neuropathological profiling in ADRD.

neuroscience↗

bioRxiv2025

Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology

The gut microbiome modulates metabolic and neurovascular processes implicated in Alzheimers disease and related dementias (ADRD), but the underlying mechanisms remain unclear. Here, we identify the bacterial metabolite imidazole propionate (ImP) as a modifier of ADRD pathology. In a cohort of 1,196 cognitively unimpaired adults, higher plasma ImP levels were associated with lower preclinical cognitive scores and biomarkers of ADRD, both cross-sectionally and longitudinally. Fecal metagenomic analysis linked putative ImP producers to ADRD phenotypes. Genome-wide integrative analysis revealed a locus on chromosome 12 associated with both plasma ImP levels and AD risk in humans, supporting a host genetic contribution to ImP regulation and a causal role of this metabolite in AD. In mice, chronic ImP administration exacerbated AD-like pathology. Mechanistically, ImP impaired brain endothelial barrier and promoted tau hyperphosphorylation in primary neurons, an effect blocked by glycogen synthase kinase-3{beta} inhibition. Together, our study links ImP to hallmarks of neurodegeneration and suggest that targeting ImP may represent a potential strategy to modify ADRD risk.

pathology↗

bioRxiv2025

Sex-Specific Differential DNA Methylation in Mild Cognitive Impairment and Alzheimers Disease

Sex differences in late-onset Alzheimers disease (AD) progression include accelerated decrements in cognitive status and greater amyloid and tau biomarker burdens in females. To identify sex-specific differentially methylated positions (DMPs) and genes in persons with mild cognitive impairment (MCI) and AD, we analyzed whole genome methylation sequencing on blood samples from participants with MCI (N=99, 52% female), AD (N=109, 43% female), and those cognitively unimpaired (CU; N=174, 52% female). Ninety-four percent of DMPs from MCI vs. CU, AD vs. CU, and AD vs. MCI pairwise comparisons were sex-specific. Female-specific DMPs were enriched in neurologic gene sets (e.g., synaptic membrane, ion channel complex), while male-specific DMPs showed limited enrichment. Sex-specific DMPs overlapped blood-specific enhancers, promoters, and transcription factor binding motifs, highlighting divergent epigenetic regulation by sex. These findings identify sex-specific genes and molecular pathways in MCI and AD and support that blood DNA methylation levels can distinguish cognitive status.

genomics↗

bioRxiv2025

Chromosome-Specific Aneuploidy Engineering via dCas9-Induced Centromeric Chromatin Relaxation

Aneuploidy, the gain or loss of chromosomes, is prevalent in both normal and disease conditions, however, experimental approaches to engineer and study aneuploidy remain limited, leaving its functional significance under-characterized. Here, we present CRISPR-Taiji (CRISPRt), an efficient method for inducing chromosome-specific mis-segregation and aneuploidy generation across all 24 human chromosomes via dead Cas9 (dCas9)-induced centromeric chromatin relaxation. Using CRISPRt with scRNA-seq, we generated the first comprehensive transcriptomic alteration landscape of nearly all autosomal aneuploidies at chromosome-arm resolution. This genotype-phenotype map provides causal evidence linking recurrent aneuploidies in clear cell renal cell carcinoma (ccRCC) to molecular and clinical phenotypes observed in patient tumors. Notably, chromosome 3(p) loss, the ccRCC initiating event, specifically drives strong interferon signaling activation, offering novel insights into ccRCC tumorigenesis and immune modulation. Overall, we establish CRISPRt as a simple, efficient and scalable approach for chromosome-specific aneuploidy engineering and characterization in preclinical models to advance aneuploidy research across diverse biological contexts.

genomics↗

bioRxiv2024

Telomere length and cognitive function among middle-aged and older participants from communities underrepresented in aging research: A preliminary study

ObjectiveAccelerated biological aging is a plausible and modifiable determinant of dementia burden facing minoritized communities, but is not well-studied in these historically underrepresented populations. Our objective was to preliminarily characterize relationships between telomere length and cognitive health among American Indian/Alaska Native (AI/AN) and Black/African American (B/AA) middle-aged and older adults. MethodsThis study included data on telomere length and cognitive test performance from 187 participants, enrolled in one of two community-based cognitive aging cohorts and who identified their primary race as AI/AN or B/AA. ResultsNested multivariable regression models revealed preliminary evidence for associations between telomere length and cognitive performance, and these associations were partially independent of chronological age. DiscussionSmall sample size limited estimate precision, however, findings suggest future work on telomere length and cognitive health in underrepresented populations at high risk for dementia is feasible and valuable as a foundation for social and behavioral intervention research.

neuroscience↗

bioRxiv2024

Whole genome methylation sequencing in blood from persons with mild cognitive impairment and dementia due to Alzheimer's disease identifies cognitive status

INTRODUCTIONWhole genome methylation sequencing (WGMS) in blood identifies differential DNA methylation in persons with late-onset dementia due to Alzheimers disease (AD) but has not been tested in persons with mild cognitive impairment (MCI). METHODSWe used WGMS to compare DNA methylation levels at 25,244,219 CpG loci in 382 blood samples from 99 persons with MCI, 109 with AD, and 174 who are cognitively unimpaired (CU). RESULTSWGMS identified 9,756 differentially methylated positions (DMPs) in persons with MCI, including 1,743 differentially methylated genes encoding proteins in biological pathways related to synapse organization, dendrite development, and ion transport. 447 DMPs exhibit progressively increasing or decreasing DNA methylation levels between CU, MCI, and AD that correspond to cognitive status. DISCUSSIONWGMS identifies DMPs in known and newly detected genes in blood from persons with MCI and AD that support blood DNA methylation levels as candidate biomarkers of cognitive status.

genomics↗

bioRxiv2024

Sex, racial, and APOE-ϵ4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease

Structured AbstractO_ST_ABSINTRODUCTIONC_ST_ABSThe effects of sex, race, and Apolipoprotein E (APOE) - Alzheimers disease (AD) risk factors - on white matter integrity are not well characterized. METHODSDiffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 {+/-} 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-{varepsilon}4 carrier status. RESULTSSex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-{varepsilon}4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSIONThere are prominent differences in white matter microstructure by sex, race, and APOE- {varepsilon}4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. HighlightsO_LISex, race, and APOE-{varepsilon}4 carrier status relate to white matter microstructural integrity C_LIO_LIFemales generally have lower FAFWcorr compared to males C_LIO_LINon-Hispanic Black adults generally have lower FAFWcorr than non-Hispanic White adults C_LIO_LIAPOE-{varepsilon}4 carriers tended to have higher FW than non-carriers C_LI Research in Context Systematic ReviewThe authors used PubMed and Google Scholar to review literature that used conventional and free-water (FW)-corrected microstructural metrics to evaluate sex, race, and APOE-{varepsilon}4 differences in white matter microstructure. While studies have previously explored differences by sex and APOE-{varepsilon}4 status, less is known about racial differences and no large-scale FW-corrected analysis has been performed. InterpretationSex and race were more associated with FAFWcorr while APOE-{varepsilon}4 status was associated with FW metrics. Association, projection, limbic, and occipital transcallosal tracts showed the greatest differences. Future DirectionFuture studies to determine the biological and social pathways that lead to sex, racial, and APOE-{varepsilon}4 differences are warranted. Consent StatementAll participants provided informed consent in their respective cohort studies.

neuroscience↗

bioRxiv2023

IFNγ modestly contributes to disease progression in the Ndufs4(-/-) model of Leigh syndrome while IP10 is dispensable

Leigh syndrome (LS) is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disease characterized by severe neurologic and metabolic abnormalities. The defining feature of the disease is the presence of symmetric, bilateral, progressive necrotizing lesions in the brain stem, cerebellum, and basal ganglia. The pathogenic mechanisms underlying disease initiation and progression in LS have yet to be elucidated. Recent evidence demonstrates that the immune system plays a key role in LS pathogenesis. Treatment with the macrophage-depleting Csf1r inhibitor pexidartinib prevents disease in the Ndufs4(-/-) mouse model of LS, but the mechanisms leading to immune activation and governing disease progression remain to be elucidated. In recent work, the cytokines IFN{gamma} and IFN{gamma}-induced protein 10 (IP10) were found to be significantly elevated in Ndufs4(-/-) brainstem. Given their role as macrophage-activating factors, here we sought to assess the role of IFN{gamma} and IP10 in LS using by generating Ndufs4(-/-)/Ifng(-/-) and Ndufs4(-/-)/IP10(-/-) double knockout lines. We find that IP10 alone does not significantly impact the onset or progression of disease in the Ndufs4(-/-) model, while IFN{gamma} loss significantly, but modestly, improves survival. These data indicate that IFN{gamma} contributes to pathology, but that IFN{gamma} and IP10 are both dispensable for overall disease course of LS. Our findings support some role for IFN{gamma} targeting therapies in the management of mitochondrial disease, but suggest they may provide only modest benefits, at least in LS.

pathology↗

bioRxiv2023

Peripheral macrophages causally contribute to disease onset and progression in the Ndufs4(KO) model of Leigh syndrome

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common paediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony stimulating factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1r{Delta}FIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1r{Delta}FIRE allele ablates microglia in both control and Ndufs4(-/-) animals, but onset of CNS lesions and sequalae in the Ndufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis disease in the Ndufs4(-/-) model.

pathology↗

bioRxiv2022

Genetic, clinical underpinnings of subtle early brain change along Alzheimer's dimensions

Alzheimers disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised clustering technique known as Surreal-GAN, through which we identified two dominant dimensions of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the "diffuse-AD" (R1) dimension shows widespread brain atrophy, and the "MTL-AD" (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE {varepsilon}4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were "druggable genes" for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE {varepsilon}4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction - driven by genes different from APOE - which may collectively contribute to the early pathogenesis of AD.

bioengineering↗

bioRxiv2022

Inducing Specific Chromosome Mis-Segregation in Human Cells

Cancer cells display persistent underlying chromosomal instability that results in chromosome mis-segregation, the formation of micronuclei, and abnormal numbers of chromosomes (aneuploidy). These features are common to nearly all human cancers, with individual tumour types intriguingly exhibiting characteristic subsets of whole, and sub-chromosomal aneuploidies. To date, few methods to induce specific aneuploidies at will exist, hampering the investigation of functional consequences of recurrent aneuploidies. Moreover, although some human cell lines with specific aneuploidies exist, the acute cellular responses to specific chromosomal instability events remain unknown. We therefore investigated the possibility of sabotaging the mitotic segregation of specific chromosomes using nuclease-dead CRISPR-Cas9 (dCas9) as a cargo carrier to specific genomic loci. We recruited the kinetochore-nucleating domain of centromere protein CENP-T to assemble ectopic kinetochores either near the centromere of chromosome 9, or the telomere of chromosome 1. Ectopic kinetochore assembly led to increased chromosome instability and aneuploidy of the target chromosomes, providing the potential to create designer karyotypes and study their immediate downstream cellular responses in a wide range of cell types. Overall, our findings provide new insights into ectopic kinetochore biology, and also represent an important step towards investigating the role of specific aneuploidy and chromosome mis-segregation events in diseases associated with aneuploidy.

cell biology↗

bioRxiv2021

Leukocyte proliferation mediates disease pathogenesis in the Ndufs4(KO) mouse model of Leigh syndrome

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of Leigh syndrome. Directly depleting leukocytes with a colony-stimulating factor 1 receptor (CSF1R) inhibitor dramatically attenuates disease, including complete prevention of CNS lesion formation and substantial extension of survival. Leukocyte depletion rescues a range of symptoms including hyperlactemia, seizures, respiratory function, and neurologic symptoms. These data provide a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement directly drives disease. These findings have significant implication for the mechanisms of disease resulting from mitochondrial dysfunction, and may lead to novel therapeutic strategies. One-Sentence SummaryPharmacologic targeting of leukocytes prevents CNS lesions, neurological disease, and metabolic dysfunction in the Ndufs4(KO) mouse model of Leigh syndrome.

pathology↗

bioRxiv2021

CSF metabolites associate with CSF tau and improve prediction of Alzheimer's disease status

INTRODUCTIONCerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated tau (p-tau) are biomarkers of Alzheimers disease (AD), yet much is unknown about AD-associated changes in tau metabolism and tau tangle etiology. METHODSWe assessed the variation of t-tau and p-tau explained by 38 previously identified CSF metabolites using linear regression models in middle-age controls from the Wisconsin Alzheimers Disease Research Center, and predicted AD/mild cognitive impairment (MCI) vs. an independent set of older controls using metabolites selected by the least absolute shrinkage and selection operator (LASSO). RESULTSThe 38 CSF metabolites explained 70.3% and 75.7% of the variance in t-tau and p-tau. Of these, 7 LASSO-selected metabolites improved the prediction ability of AD/MCI vs. older controls (AUC score increased from 0.92 to 0.97 and 0.78 to 0.93) compared to the base model. DISCUSSIONThese tau-correlated CSF metabolites increase AD/MCI prediction accuracy and may provide insight into tau tangle etiology.

molecular biology↗

bioRxiv2020

Mechanisms underlying neonate specific metabolic effects of volatile anesthetics

Volatile anesthetics (VAs) are widely used in medicine, but the mechanisms underlying their effects remain ill-defined. Though routine anesthesia is safe in healthy individuals, instances of sensitivity are well-documented, and there has been significant concern regarding the impact of VAs on neonatal brain development. Evidence indicates that VAs have multiple targets, with anesthetic and non-anesthetic effects mediated by neuroreceptors, ion channels, and the mitochondrial electron transport chain. Here, we characterize an unexpected metabolic effect of VAs in neonatal mice. Neonatal blood {beta}-hydroxybutarate ({beta}-HB) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia. {beta}-HB in adults, including animals in dietary ketosis, is unaffected. Depletion of {beta}-HB is mediated by citrate accumulation, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation. Adults show similar significant changes to citrate and malonyl-CoA, but are insensitive to malonyl-CoA, displaying reduced metabolic flexibility compared to younger animals.

physiology↗

bioRxiv2020

Modelling the effects of lymph node swelling on T-cell response

Swelling of lymph nodes is commonly observed during the adaptive immune response, yet the impact on T cell trafficking and subsequent immune response is not well known. To better understand the effect of macro-scale alterations, we developed an agent-based model of the lymph node para-cortex, describing T cell trafficking and response to antigen-presenting dendritic cells alongside swelling-induced changes in T cell recruitment and egress, and regulation of expression of egress-modulating T cell receptor Sphingosine-1-phosphate receptor-1. Analysis of effector T cell response under varying swelling conditions showed that swelling consistently aided T cell activation. However, subsequent effector CD8+ T cell production could be reduced if swelling occurred too early in the T cell proliferative phase or if T cell cognate frequency was low due to increased opportunity for T cell exit. Temporarily extending retention of newly differentiated effector T cells, mediated by Sphingosine-1-phosphate receptor-1 expression, mitigated any negative effects of swelling by allowing facilitation of activation to outweigh increased access to exit areas. These results suggest targeting temporary effector T cell retention and egress associated with swelling may offer new ways to modulate effector TC responses in, for example, immuno-suppressed patients and optimisation of vaccine design.

immunology↗