Biology subjects

Chang, J. T.

Publications and source records attributed to Chang, J. T..

22 records · Page 2Linked to original sources

bioRxiv2020

Functional delineation of tissue-resident CD8 T cell heterogeneity during infection and cancer

Unremitting defense against diverse pathogens and malignancies requires a dynamic and durable immune response. Tissue-resident memory CD8+ T cells (TO_SCPLOWRMC_SCPLOW) afford robust protection against infection and cancer progression through continuous surveillance of non-lymphoid tissues. Here, we provide insight into how TO_SCPLOWRMC_SCPLOW confer potent and persistent immunity through partitioning of distinct cellular subsets differing in longevity, effector function, and multipotency. Antigen-specific CD8+ T cells localized to the epithelium of the small intestine are primarily comprised of a shorter-lived effector population most prominent early following both acute viral and bacterial infections, and a longer-lived Id3hi TO_SCPLOWRMC_SCPLOW population that subsequently accumulates at later memory timepoints. We define regulatory gene-programs driving these distinct TO_SCPLOWRMC_SCPLOW states, and further clarify roles for Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal TO_SCPLOWRMC_SCPLOW heterogeneity during infection. Further, through single-cell RNAseq analysis we demonstrate that tumor-infiltrating lymphocytes broadly differentiate into discrete populations of short-lived and long-lived TO_SCPLOWRMC_SCPLOW-like subsets, which share qualities with terminally-exhausted and progenitor-exhausted cells, respectively. As the clinical relevance of TO_SCPLOWRMC_SCPLOW continues to widen from acute infections to settings of chronic inflammation and malignancy, clarification of the spectrum of phenotypic and functional states exhibited by CD8+ T cells that reside in non-lymphoid tissues will provide a framework for understanding their regulation and identity in diverse pathophysiological contexts.

immunology↗

bioRxiv2019

Experience-dependent reorganization drives the development of a binocularly unified representation of orientation in ferret visual cortex

Across sensory areas, neural microcircuits consolidate diverse streams of information into unified, representations of the external world. In the carnivore visual cortex, where eye-specific inputs converge, it has been posited that a single, shared columnar representation of orientation develops independent of sensory experience. In this study, in vivo calcium imaging with columnar and cellular resolution reveals a strikingly different developmental process in ferret visual cortex, starting with an early developmental period in which contralateral, ipsilateral or binocular stimulation each yield distinct well-organized representations of orientation that are misaligned at the columnar and cellular scale. Experience-dependent processes drive the reorganization of these three representations towards a single binocularly-aligned representation resembling the early binocular representation through concerted shifts in the preferred orientation of individual neurons. Thus, contrary to previous findings, a unified binocular representation of orientation results from an experience-dependent process that aligns the activity patterns of three distinct neural representations.

neuroscience↗

bioRxiv2019

Chemical Impacts of the Microbiome Across Scales Reveal Novel Conjugated Bile Acids

A mosaic of cross-phyla chemical interactions occurs between all metazoans and their microbiomes. In humans, the gut harbors the heaviest microbial load, but many organs, particularly those with a mucosal surface, associate with highly adapted and evolved microbial consortia1. The microbial residents within these organ systems are increasingly well characterized, yielding a good understanding of human microbiome composition, but we have yet to elucidate the full chemical impact the microbiome exerts on an animal and the breadth of the chemical diversity it contributes2. A number of molecular families are known to be shaped by the microbiome including short-chain fatty acids, indoles, aromatic amino acid metabolites, complex polysaccharides, and host lipids; such as sphingolipids and bile acids3-11. These metabolites profoundly affect host physiology and are being explored for their roles in both health and disease. Considering the diversity of the human microbiome, numbering over 40,000 operational taxonomic units12, a plethora of molecular diversity remains to be discovered. Here, we use unique mass spectrometry informatics approaches and data mapping onto a murine 3D-model13-15 to provide an untargeted assessment of the chemical diversity between germ-free (GF) and colonized mice (specific-pathogen free, SPF), and report the finding of novel bile acids produced by the microbiome in both mice and humans that have evaded characterization despite 170 years of research on bile acid chemistry16.

microbiology↗

bioRxiv2017

Potassium channels contribute to activity-dependent scaling of dendritic inhibition

GABAergic inhibition plays a critical role in the regulation of neuronal activity. In the neocortex, inhibitory interneurons that target the dendrites of pyramidal cells influence both electrical and biochemical postsynaptic signaling. Voltage-gated ion channels strongly shape dendritic excitability and the integration of excitatory inputs, but their contribution to GABAergic signaling is less well understood. By combining 2-photon calcium imaging and focal GABA uncaging, we show that voltage-gated potassium channels normally suppress the GABAergic inhibition of calcium signals evoked by back-propagating action potentials in dendritic spines and shafts of cortical pyramidal neurons. Moreover, the voltage-dependent inactivation of these channels leads to enhancement of dendritic calcium inhibition following somatic spiking. Computational modeling reveals that the enhancement of calcium inhibition involves an increase in action potential depolarization coupled with the nonlinear relationship between membrane voltage and calcium channel activation. Overall, our findings highlight the interaction between intrinsic and synaptic properties and reveal a novel mechanism for the activity-dependent scaling of GABAergic inhibition.\n\nSignificance StatementGABAergic inhibition potently regulates neuronal activity in the neocortex. How such inhibition interacts with the intrinsic electrophysiological properties of single neurons is not well-understood. Here we investigate the ability of voltage-gated potassium channels to regulate the impact of GABAergic inhibition in the dendrites of neocortical pyramidal neurons. Our results show that potassium channels normally reduce inhibition directed towards pyramidal neuron dendrites. However, these channels are inactivated by strong neuronal activity, leading to an enhancement of GABAergic potency and limiting the corresponding influx of dendritic calcium. Our findings illustrate a previously unappreciated relationship between neuronal excitability and GABAergic inhibition.

neuroscience↗