Biology subjects

Knopper, K.

Publications and source records attributed to Knopper, K..

4 recordsLinked to original sources

bioRxiv2026

Sex hormones gate the neuronal control of dendritic cell migration and immunity

How endocrine states modulate local immune responses is a fundamental question in immunology. Sexual dimorphism is a striking example: females generally mount stronger immune responses than males, yet how sex hormones intersect with local signals is poorly understood. Here, we identify an endocrine-neuro-immune circuit in which sex hormones determine whether immune cells respond to nociceptor signals. In female skin, nociceptor-derived CGRP promotes dendritic cell (DC) migration and T cell priming indirectly through inflammatory monocytes. CGRP induces monocyte production of Activin A, which upregulates CXCR4 on DCs and promotes migration to draining lymph nodes. In males, androgen receptor signaling suppresses monocyte Activin A and silences this circuit. Disrupting the relay abolishes enhanced female immunity, whereas deleting androgen receptor in male monocytes restores neuronal control. Thus, sex hormones regulate immunity by determining how immune cells interpret neuronal signals, revealing how endocrine state can gate local neuroimmune communication to generate sex-specific immune responses.

immunology↗

bioRxiv2026

Intestinal intraepithelial lymphocyte migration and tissue homeostasis are dictated by Gα13

Intestinal intraepithelial lymphocytes (IEL), including conventional CD8{beta} T resident memory (Trm) cells and unconventional CD8 T cells, promote tissue integrity. Here, we studied the G-protein coupled receptor signals regulating IEL positioning, homeostasis, and function. Deficiency in heterotrimeric G-protein subunit G13 or its effector Arhgef1 caused an intestine-specific loss of all types of CD8+ TCR{beta} and TCR{gamma}{delta} IEL. G13-deficient IEL exhibited restricted intraepithelial movement and impaired maturation. Induction of intestinal CD8{beta}+ Trm upon infection was intact in the absence of G13-signaling, but the cells had poor access to the villous niche and defective survival that could be rescued by increasing TGF{beta}+ or interleukin (IL)15. In vivo CRISPR/Cas9 screening identified GPR132 as a G13-coupled receptor that regulates CD8{beta}+ IEL homeostasis and migration to lysophosphatidylcholine. Mice bearing G13-deficient T cells suffered more severe colitis and increased colorectal tumor growth. The selective requirement for G13-signaling for IEL positioning and survival in the villous niche has implications for therapeutic intervention.

immunology↗

bioRxiv2026

ABCC1 protects skin dendritic cells from FITC-induced toxicity by efflux and extracellular glutathione buffering

Dendritic cell (DC) migration is critical for initiating adaptive immune responses. Previous work suggested a role for ATP-binding cassette transporter C1 (ABCC1) in skin DC migration following cutaneous fluorescein isothiocyanate (FITC) exposure, but the precise mechanism involved was unclear. Here we establish that the primary contribution of ABCC1 to skin DC function following FITC exposure is not modulation of migration, but enhancement of survival. Our findings demonstrate that ABCC1 operates on a dual level: intracellularly, by transporting toxic FITC and fluorescein out of DCs, and extracellularly, by contributing to a glutathione (GSH) buffer zone that protects surrounding cells. DCs are particularly susceptible to FITC-mediated toxicity, possibly due to their high endocytic activity. This study elucidates the critical dependence of DCs on ABCC1 and extracellular GSH for resistance to toxic organic molecules and thereby identifies potential therapeutic avenues targeting ABCC1 to modulate immune responses. Significance StatementAdaptive immunity is critically dependent on dendritic cells (DCs) and their ability to take up foreign molecules for processing and presentation to T cells. DCs in the skin are exposed to a diversity of environmental chemicals and whether they have mechanisms to protect themselves from chemical-induced toxicity has been unclear. In this work we investigate the role of the multi-drug resistance transporter ABCC1 (MRP1) in DC biology. We reveal that ABCC1 shields DCs from chemical poisoning following skin exposure to fluorescein isothiocyanate (FITC). ABCC1 is needed both cell intrinsically and cell extrinsically to achieve the full protective effect. This discovery underscores a previously unrecognized reliance of DCs on ABCC1 function and opens new opportunities for therapeutic manipulation of these cells.

immunology↗

bioRxiv2023

Cytotoxic CNS-associated T cells drive axon degeneration by targeting perturbed myelinating oligodendrocytes in PLP1 mutant mice

Myelin defects lead to neurological dysfunction in various diseases and in normal aging. Chronic neuroinflammation often contributes to axon-myelin damage in these conditions and can be initiated and/or sustained by perturbed myelinating glia. We have previously shown that distinct mutations in the PLP1 gene result in neurodegeneration that is largely driven by adaptive immune cells. Here we characterize CD8+ CNS-associated T cells in these myelin mutants using single-cell transcriptomics and identify population heterogeneity and disease-associated changes. We demonstrate that early sphingosine-1-phosphate receptor modulation attenuates the recruitment of T cells and neural damage, while later targeting of CNS-associated T cell populations is inefficient and has no effect on neurodegeneration. Applying bone marrow chimerism and utilizing random X chromosome inactivation, we provide evidence that axonal damage is driven by cytotoxic, antigen specific CD8+ T cells that target mutant myelinating oligodendrocytes. These findings offer insights into neural-immune interactions and are of translational relevance for neurological conditions associated with myelin defects and neuroinflammation.

neuroscience↗