Biology subjects

Mroz, N. M.

Publications and source records attributed to Mroz, N. M..

5 recordsLinked to original sources

bioRxiv2025

The phosphatases TCPTP, PTPN22, and SHP1 play unique roles in T cell phosphotyrosine maintenance and feedback regulation of the TCR

The protein tyrosine phosphatases (PTPs) TCPTP, PTPN22, and SHP1 are critical regulators of the activating phosphotyrosine (pY) site on the initiating T cell kinase, LckY394. Still, the broader implications of these phosphatases in T cell receptor (TCR) signalling and T cell biology remain unclear. By combining CRISPR/Cas9 gene editing and mass spectrometry, we evaluate the protein- and pY-level effects of TCPTP, PTPN22, and SHP1 in the Jurkat T cell model system. We find that deletion of each phosphatase corresponds to unique changes in the proteome of T cells, with few large-scale changes to TCR signalling proteins. Notably, PTPN22 and SHP1 deletions have opposing effects on pY abundance globally, while TCPTP deletion modestly elevates pY levels. Finally, we show that TCPTP is indirectly involved in Erk1/2 positive feedback to the TCR. Overall, our work provides evidence for alternative functions of three T cell phosphatases long thought to be redundant.

systems biology↗

bioRxiv2024

Type 1 lymphocytes and interferon-γ accumulate in the thalamus and restrict seizure susceptibility after traumatic brain injury

Chronic neural circuit hyperexcitability frequently emerges after brain injury, but endogenous mechanisms constraining runaway activity remain poorly understood. Here, we reveal that the adaptive immune system acts as a homeostatic brake on network excitability following traumatic brain injury (TBI). In mice, cortical trauma triggered a delayed infiltration of interferon-{gamma} (IFN{gamma})-producing type 1 lymphocytes into the sensory thalamus. Rather than driving pathology, IFN{gamma} signaling directly in neurons restricted thalamocortical network hyperexcitability. This protective axis was tonically regulated; depleting CD4 T cells de-repressed local non-CD4 type 1 lymphocytes, elevating IFN{gamma} signaling and protecting from seizures. A single dose of exogenous IFN{gamma} abolished hypersynchronous circuit bursting and rescued injury-induced seizure incidence, severity, and mortality, establishing a therapeutic framework for safeguarding circuit stability after brain injury.

immunology↗

bioRxiv2024

Dynamic fibroblast-immune interactions shape wound healing after brain injury

Fibroblasts coordinate the response to tissue injury, directing organ regeneration versus scarring. In the central nervous system (CNS), fibroblasts are uncommon cells enriched at tissue borders, and their molecular, cellular, and functional interactions after brain injury are poorly understood. Here we define the fibroblast response to sterile brain damage across time and space. Early pro-fibrotic myofibroblasts infiltrated CNS lesions and were functionally and spatially organized by fibroblast TGF{beta} signaling, pro-fibrotic macrophages and microglia, and perilesional brain glia that activated TGF{beta} via integrin v{beta}8. Early myofibroblasts subsequently transitioned into a variety of late states, including meningeal and lymphocyte-interactive fibroblasts that persisted long term. Interruption of this dynamic fibroblast-macrophage-glial coordination impaired brain wound healing and the resolution of neuroinflammation, disrupted generation of late de novo CNS lymphocyte niches, and increased mortality in a stroke model. This work highlights an unexpected role of fibroblasts as coordinate regulators of CNS healing and neuroinflammation after brain injury.

immunology↗

bioRxiv2023

Group 2 innate lymphoid cells constrain type 3/17 lymphocytes in shared stromal niches to restrict liver fibrosis

Group 2 innate lymphoid cells (ILC2s) cooperate with adaptive Th2 cells as key organizers of tissue type 2 immune responses, while a spectrum of innate and adaptive lymphocytes coordinate early type 3/17 immunity. Both type 2 and type 3/17 lymphocyte associated cytokines are linked to tissue fibrosis, but how their dynamic and spatial topographies may direct beneficial or pathologic organ remodelling is unclear. Here we used volumetric imaging in models of liver fibrosis, finding accumulation of periportal and fibrotic tract IL-5+ lymphocytes, predominantly ILC2s, in close proximity to expanded type 3/17 lymphocytes and IL-33high niche fibroblasts. Ablation of IL-5+ lymphocytes worsened carbon tetrachloride-and bile duct ligation-induced liver fibrosis with increased niche IL-17A+ type 3/17 lymphocytes, predominantly {gamma}{delta} T cells. In contrast, concurrent ablation of IL-5+ and IL-17A+ lymphocytes reduced this progressive liver fibrosis, suggesting a cross-regulation of type 2 and type 3 lymphocytes at specialized fibroblast niches that tunes hepatic fibrosis.

immunology↗

bioRxiv2023

Group 2 innate lymphoid cells promote inhibitory synapse development and social behavior

The innate immune system plays essential roles in brain synaptic development, and immune dysregulation is implicated in neurodevelopmental diseases. Here we show that a subset of innate lymphocytes (group 2 innate lymphoid cells, ILC2s) is required for cortical inhibitory synapse maturation and adult social behavior. ILC2s expanded in the developing meninges and produced a surge of their canonical cytokine Interleukin-13 (IL-13) between postnatal days 5-15. Loss of ILC2s decreased cortical inhibitory synapse numbers in the postnatal period where as ILC2 transplant was sufficient to increase inhibitory synapse numbers. Deletion of the IL-4/IL-13 receptor (Il4ra) from inhibitory neurons phenocopied the reduction inhibitory synapses. Both ILC2 deficient and neuronal Il4ra deficient animals had similar and selective impairments in adult social behavior. These data define a type 2 immune circuit in early life that shapes adult brain function. One sentence summaryType 2 innate lymphoid cells and Interleukin-13 promote inhibitory synapse development.

neuroscience↗