Biology subjects

Kaur, S. P.

Publications and source records attributed to Kaur, S. P..

3 recordsLinked to original sources

bioRxiv2026

Gut-Associated Metabolites (GAMs) revitalize dysfunctional CD8⁺ T lymphocytes in Osteosarcoma

Osteosarcoma (OS) is one of the top ranking and deadliest primary malignant bone tumor of youngsters and adolescents. OS has poor prognostic features due to its immunosuppressive "cold" tumor microenvironment, obstructing the anti-tumor effector functions of immune cells (including cytotoxic CD8 T lymphocytes). Recent developments have focused on the role of Gut Microbiota in modulating effector immune responses in various cancers. However, the immunomodulatory role of gut microbiota and its derived gut-associated metabolites (GAMs) in OS still remains unclear. Here we report that peripheral CD8 T lymphocytes in osteosarcoma patients are less frequent in circulation, hypo-producers of effector cytokines (IFN-{gamma} and TNF-), and have compromised metabolic fitness. We characterized and investigated the effect of a panel of microbiota-derived GAMs on CD8 T lymphocytes, confirming their immunomodulatory role with respect to CD8 T lymphocytes activation, cellular metabolism and effector functions. Indole-3-lactic acid (ILA; product of tryptophan metabolism), was observed to be the strongest immunostimulant among all the GAMs studied. ILA enhanced the anti-tumor effector functions of CD8 T lymphocytes through increased glucose uptake, a higher mitochondrial bio-mass and increased production of IFN-{gamma} and TNF-. Moreover, ILA-primed cytotoxic T lymphocytes exhibited considerably higher cytotoxicity and increased apoptosis of osteosarcoma cells (U2OS). Altogether, our data demonstrates that ILA acts as a microbial-derived immune modulator to metabolically reprogram and restore dysfunctional CD8 T lymphocytes against osteosarcoma. This study for the first time demonstrates the therapeutic potential of exploiting the nexus between "Gut-Immune-Bone Tumor" ternary as a safe and cost-effective combinatorial immunotherapy against osteosarcoma. Graphical AbstractIndole-3-Lactic Acid (ILA) Reinvigorates CD8+ T-Cell Immunity in Osteosarcoma Circulating CD8+ T cells from osteosarcoma patients exhibit impaired metabolic fitness, reduced effector cytokine production, and diminished tumoricidal activity. Screening of gut-associated metabolites identified the microbial tryptophan metabolite indole-3-lactic acid (ILA) as the most potent immunomodulator. ILA restores glucose uptake and mitochondrial biomass, enhances IFN-{gamma} and TNF- production, promotes polyfunctional CD8+ T-cell responses, and significantly improves CTL-mediated killing of osteosarcoma cells, highlighting its potential as a microbiota-derived immunometabolic therapeutic for osteosarcoma. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/741694v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@19809aforg.highwire.dtl.DTLVardef@a3eb09org.highwire.dtl.DTLVardef@19bada3org.highwire.dtl.DTLVardef@1a4c4da_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2025

ILC3 inhibits Osteoclastogenesis and ameliorates Inflammatory Bone Loss in Post-menopausal Osteoporosis

Although the significance of T lymphocytes in maintaining bone homeostasis is well established, the role of innate lymphoid cells (ILCs), the innate counterparts of T cells, in maintaining bone homeostasis is uncertain. In this study, we examined, for the first time, the anti-osteoclastogenic property of ILC3 in vitro. We observed that ILC3 inhibits RANKL-mediated osteoclastogenesis in a cell ratio-dependent manner. We further employed an ovariectomized (ovx) mouse model, which mimics postmenopausal osteoporosis (PMO), to investigate the role of ILC3 in inflammatory bone loss. Notably, our in vivo data unequivocally validate that the ovx mice have a markedly lower frequency of ILC3 in the bone marrow (BM). Furthermore, the temporal-kinetic analysis revealed that alterations in ILC3 cell dynamics and function in the BM are associated with the development and progression of inflammatory bone loss in PMO. Additionally, our in vivo results demonstrate that dysbiosis in PMO drives significant alterations in the frequency of ILC3 subsets by promoting the expansion of IL-17-producing Nkp46- ILC3 and inhibiting the development of IL-22-producing Nkp46+ ILC3. Moreover, T-bet+ ILC3s are significantly increased in ovariectomized (ovx) mice. Altogether, the present study for the first time, reports the critical role of dysregulated ILC3 in the progression of PMO and offers a novel immunotherapeutic approach targeting ILC3 for treating and managing PMO. Graphical abstractPMO is associated with leaky gut and dysbiosis, which leads to a deficiency of SCFAs in the ovx mice. Dysbiosis in ovx mice disturbs the homeostatic balance of the ILC3 with an increase in IL-17-producing ILC3 and a decrease in IL-22-producing ILC3. Further Tbet expression is enhanced in the ILC3 of the ovx mice, which is associated with disease pathogenesis. Additionally, IL-2 expression is decreased in the ILC3 of the ovx mice. Decreased expression of ILC3 migratory molecules reduced the migration of ILC3 in bone marrow. ILC3 inhibits osteoclast differentiation. However, in the case of ovx mice, ILC3 are compromised and promote osteoclastogenesis. O_FIG O_LINKSMALLFIG WIDTH=154 HEIGHT=200 SRC="FIGDIR/small/677486v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@10543ccorg.highwire.dtl.DTLVardef@a6452dorg.highwire.dtl.DTLVardef@798f8org.highwire.dtl.DTLVardef@cc026c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Broken force dispersal network in tip-links by the mutations induces hearing-loss

Tip-link as force-sensor in the hearing conveys the mechanical force originating from sound to ion-channels while maintaining the integrity of the entire sensory assembly in inner-ear. This delicate balance between structure and function of tip-links is regulated by Ca2+-ions present in endolymph. Mutations at the Ca2+-binding sites of tip-links often lead to congenital deafness, sometimes syndromic defects impairing vision along with hearing. Although such mutations are already identified, it is still not clear how the mutants alter the structure-function properties of the force-sensors associated with diseases. With an aim to decipher the differences in force-conveying properties of the force-sensors in molecular details, we identified the conformational variability of mutant and wild-type tip-links at the single-molecule level using FRET at the endolymphatic Ca2+ concentrations and subsequently measured the force-responsive behavior using single-molecule force spectroscopy with an AFM. AFM allowed us to mimic the high and wide range of force ramps (103 - 106 pN.s-1) as experienced in the inner ear. We performed in silico network analyses to learn that alterations in the conformations of the mutants interrupt the natural force-propagation paths through the sensors and make the mutant tip-links vulnerable to input forces from sound stimuli. We also demonstrated that a Ca2+ rich environment can restore the force-response of the mutant tip-links which may eventually facilitate the designing of better therapeutic strategies to the hearing loss.\n\nSignificance StatementForce-sensors in inner ear are the key components in the hearing. Mutations in force-sensors often lead to congenital hearing loss. Loss of hearing has become a threat to humanity, with over 5% of world population suffering from deafness and 40% of which is congenital, primarily due to mutations in the sensory machinery in inner-ear. A better understanding of the molecular mechanism of the underlined hearing loss due to mutations is, therefore, necessary for better therapeutics to deaf. Here with a zoomed region of the force-sensors, we pointed out the differences in the force-propagation properties of the mutant and wild-type force-sensors. Our observation on restoring of functions of mutants in Ca2+-rich buffer indicates methods of developing low-cost therapeutic strategies against deafness.

biophysics↗