Biology subjects

Jankovic, D.

Publications and source records attributed to Jankovic, D..

7 recordsLinked to original sources

bioRxiv2025

Gelatinase activity is required for Muller glia morphogenesis and neuronal maintenance in the retina

Glial cells are indispensable support elements of the nervous system, yet the mechanisms by which they integrate into densely packed, extracellular matrix (ECM)-rich cellular environments remain poorly understood. In the retina, Muller glia (MG) serve as the principal support cells, performing roles analogous to astrocytes in the brain. As late-born retinal cells, MG undergo morphogenesis within a complex extracellular milieu composed of neighbouring neurons, synapses, and ECM components. Using the zebrafish retina, we show that developing MG dynamically interact with the ECM across all retinal layers while expressing the ECM-remodelling enzymes matrix metalloproteinases (Mmp) 2 and 9. Although Mmps are known to contribute to tissue remodelling and disease processes such as glioma invasion, their developmental roles in glia remain less defined. Here, we demonstrate that Mmp2 and Mmp9 are required for MG morphogenesis and glia-neuron integration. Pharmacological inhibition or genetic loss of mmp2 and mmp9 impaired MG outgrowth and reduced process complexity within synaptic layers, leading to decreased MG-synapse associations. Double mutants (mmp2-/-;mmp9-/-) displayed normal neuronal development and visual function at larval stages but exhibited gliosis, premature neurodegeneration, and visual deficits in adulthood. Together, these findings reveal that Mmp2 and Mmp9 are critical for establishing MG-synapse interactions during development and for maintaining neuronal integrity and visual function in the mature retina.

neuroscience↗

bioRxiv2025

Single-cell profiling of human bone marrow reveals multiple myeloma progression is accompanied by an increase in CD56bright bone marrow resident NK cells.

Natural killer (NK) cells play a key role in the innate immune response against tumour progression. While the immune microenvironment in multiple myeloma (MM) becomes increasingly dysfunctional during disease evolution, little is known about changes in the NK cell compartment. Using primary samples from clinical trial patients, we performed detailed phenotypic analyses of bone marrow mononuclear cells from MGUS, SMM, and newly diagnosed MM patients. We found that disease progression is associated with an increase in CD56bright NK cells with a dynamic positive association between this NK cell subset and local tumour burden. We generated a large single-cell RNA sequencing dataset of >100,000 NK cells from healthy donor individuals and plasma cell disorder patients and identify a bone marrow specific CD56bright-like NK cell population (BM-NK) that is enriched in the marrow of MM patients. These findings highlight the evolution of the NK-cell compartment in MM and suggest a role for BM-resident CD56bright NK cells with impaired cytotoxicity in promoting immune evasion.

cancer biology↗

bioRxiv2023

Pre-existing interferon gamma conditions the lung to mediate early control of SARS-CoV-2

Interferons (IFNs) are critical for anti-viral host defence. Type-1 and type-3 IFNs are typically associated with early control of viral replication and promotion of inflammatory immune responses; however, less is known about the role of IFN{gamma} in anti-viral immunity, particularly in the context of SARS-CoV-2. We have previously observed that lung infection with attenuated bacteria Mycobacterium bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 (SCV2) infection and disease in two mouse models. Assessment of the pulmonary cytokine milieu revealed that iv BCG induces a robust IFN{gamma} response and low levels of IFN{beta}. Here we examined the role of ongoing IFN{gamma} responses due to pre-established bacterial infection on SCV2 disease outcomes in two murine models. We report that IFN{gamma} is required for iv BCG induced reduction in pulmonary viral loads and that this outcome is dependent on IFN{gamma} receptor expression by non-hematopoietic cells. Further analysis revealed that BCG infection promotes the upregulation of interferon-stimulated genes (ISGs) with reported anti-viral activity by pneumocytes and bronchial epithelial cells in an IFN{gamma}-dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirmed the importance of IFN{gamma} in these anti-viral effects by demonstrating that the recombinant cytokine itself provides strong protection against SCV2 challenge when administered intranasally. Together, our data show that a pre-established IFN{gamma} response within the lung is protective against SCV2 infection, suggesting that concurrent or recent infections that drive IFN{gamma} may limit the pathogenesis of SCV2 and supporting possible prophylactic uses of IFN{gamma} in COVID-19 management.

immunology↗

bioRxiv2022

Attenuated humoral responses in HIV infection after SARS-CoV-2 vaccination are linked to global B cell defects and cellular immune profiles

People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can have residual immune dysfunction and often display poorer responses to vaccination. We assessed in a cohort of PLWH (n=110) and HIV negative controls (n=64) the humoral and spike-specific B-cell responses following 1, 2 or 3 SARS-CoV-2 vaccine doses. PLWH had significantly lower neutralizing antibody (nAb) titers than HIV-negative controls at all studied timepoints. Moreover, their neutralization breadth was reduced with fewer individuals developing a neutralizing response against the Omicron variant (BA.1) relative to controls. We also observed a delayed development of neutralization in PLWH that was underpinned by a reduced frequency of spike-specific memory B cells (MBCs) and pronounced B cell dysfunction. Improved neutralization breadth was seen after the third vaccine dose in PLWH but lower nAb responses persisted and were associated with global, but not spike-specific, MBC dysfunction. In contrast to the inferior antibody responses, SARS-CoV-2 vaccination induced robust T cell responses that cross-recognized variants in PLWH. Strikingly, a subset of PLWH with low or absent neutralization had detectable functional T cell responses. These individuals had reduced numbers of circulating T follicular helper cells and an enriched population of CXCR3+CD127+CD8+ T cells after two doses of SARS-CoV-2 vaccination, which may compensate for sub-optimal serological responses in the event of infection. Therefore, normalisation of B cell homeostasis could improve serological responses to vaccines in PLWH and evaluating T cell immunity could provide a more comprehensive immune status profile in these individuals and others with B cell imbalances.

immunology↗

bioRxiv2021

The skin environment controls local dendritic cell differentiation and function through innate IL-13

The signals driving the adaptation of type-2 dendritic cells (DC2s) to diverse peripheral environments are not well understood. We show that the development of CD11blow migratory DC2s, a DC2 population unique to the dermis, requires STAT6- and KLF4-dependent IL-13 signaling, whereas DC2s in lung and small intestine are STAT6-independent. Dermal IL-13 is mostly derived from innate lymphoid cells expressing a resting ICOS+ KLRG1-ST2-phenotype. Analysis of public datasets indicates that human skin DC2s also express an IL-4/IL-13 gene signature compared to blood or spleen, suggesting a similar developmental pathway in mice and humans. In the absence of IL-13 signaling, dermal DC2s are stable in number but remain CD11bhi and show defective activation in response to allergen with diminished ability to support IL-4+ GATA3+ Th development, whereas anti-fungal IL-17+ ROR{gamma}t+ responses are increased. Thus, steady-state IL-13 fosters a non-inflammatory and pro-allergic environment in healthy skin via conditioning of local DC2s.

immunology↗

bioRxiv2019

RNF144A shapes the hierarchy of cytokine signaling to provide protective immunity against influenza

Cytokine-induced signaling pathways are tightly regulated and self-limiting, as their dysregulation causes immune disorders and cancer. The precise mechanisms that fine-tune these responses are incompletely understood. We show that the E3 ubiquitin ligase RNF144A is an IL-2/STAT5-induced gene in T cells and critically orchestrates the hierarchy of IL-2R signaling to promote STAT5 activation and limit RAF-ERK-MAPK output from the IL-2R. Mechanistically, RNF144A increased the interaction between IL-2R{beta} and STAT5 and polyubiquitinated RAF1, enhancing its proteasomal degradation and preventing the formation of the potent RAF1/BRAF kinase complex. CD8+ T cells from Rnf144a-/- mice had impaired IL-2-induction of effector genes, including Tnf and granzymes, and these mice demonstrated increased susceptibility to influenza. Reduced RNF144A expression was associated with more severe influenza in humans and its expression in patients was a biomarker distinguishing moderate from severe disease. These studies reveal a vital physiological role for RNF144A in maintaining the fidelity of IL-2R signaling in CTLs to prevent severe inflammation in response to infection.\n\nOne Sentence SummaryRNF144A promotes anti-viral immunity by regulating the hierarchy of cytokine signal output

immunology↗

bioRxiv2017

Toxoplasma gondii microneme proteins 1 and 4 bind to Toll-like receptors 2 and 4 N-glycans triggering innate immune response

Infection of host cells by Toxoplasma gondii is an active process, which is regulated by secretion of microneme (MICs) and rhoptry proteins (ROPs and RONs) from specialized organelles in the apical pole of the parasite. MIC1, MIC4 and MIC6 assemble into an adhesin complex, secreted on the parasite surface and function to promote infection competency. MIC1 and MIC4 are known to bind terminal sialic acid residues and galactose residues, respectively and to induce IL-12 production from splenocytes. Here we show that rMIC1- and rMIC4-stimulated dendritic cells and macrophages to produce proinflammatory cytokines, and they do so by engaging TLR2 and TLR4. This process depends on sugar recognition, since point mutations in the carbohydrate-recognition domains (CRD) of rMIC1 and rMIC4 inhibit innate immune cells activation. HEK cells transfected with TLR2 glycomutants were selectively unresponsive to MICs. Following in vitro infection, parasites lacking MIC1 or MIC4, as well as expressing MIC proteins with point mutations in their CRD, failed to induce wild-type (WT) levels of IL-12 secretion by innate immune cells. However, only MIC1 was shown to impact systemic levels of IL-12 and IFN-{gamma} in vivo. Together, our data show that MIC1 and MIC4 interact physically with TLR2 and TLR4 N-glycans to trigger IL-12 responses, and MIC1 is playing a significant role in vivo by altering T. gondii infection competency and murine pathogenesis.\n\nAUTHOR SUMMARYToxoplasmosis is caused by the protozoan Toxoplasma gondii, belonging to the Apicomplexa phylum. This phylum comprises important parasites able to infect a broad diversity of animals, including humans. A particularity of T. gondii is its ability to invade virtually any nucleated cell of all warm-blooded animals through an active process, which depends on the secretion of adhesin proteins. These proteins are discharged by specialized organelles localized in the parasite apical region, and termed micronemes and rhoptries. We show in this study that two microneme proteins from T. gondii utilize their adhesion activity to stimulate innate immunity. These microneme proteins, denoted MIC1 and MIC4, recognize specific sugars on receptors expressed on the surface of mammalian immune cells. This binding activates these innate immune cells to secrete cytokines, which promotes efficient host defense mechanisms against the parasite and regulate their pathogenesis. This activity promotes a chronic infection by controlling parasite replication during acute infection.

immunology↗