Biology subjects

Mangione, M.

Publications and source records attributed to Mangione, M..

4 recordsLinked to original sources

bioRxiv2025

T cell-derived IFN-γ Suppresses T Follicular Helper Cell Differentiation and Antibody Responses during Viral Infections

CD4+ T cells play a critical role in antiviral humoral and cellular immune responses. We have previously reported that subcutaneous lymphocytic choriomeningitis virus (s.c. LCMV) infection is characterized by a stark compartmentalization of CD4+ T cells, leading to strong TH1 polarization but virtually absent T follicular helper (TFH) cells, a key driver of humoral immunity. Here, we investigated the mechanisms responsible for this impaired TFH differentiation. We found that T-bet+ cells induced by s.c. LCMV infection encompass a TH1 subset expressing Granzyme-B (GzmB) and a Tcf-1+ subset that retains the potential for TFH differentiation without expressing mature TFH markers. Interestingly, IFN-{gamma} blockade enables full differentiation of Tcf-1+ cells into TFH, formation of germinal centers and increased antibody production. Of note, the suppression of TFH cells by IFN-{gamma} is not directly mediated through CD4+ T cells but rather involves another cell type, likely dendritic cells (DCs). Our study provides novel insights into the mechanisms directing early CD4+ T cell polarization and affecting humoral responses to viruses, laying a foundation for the development of effective vaccine strategies.

immunology↗

bioRxiv2023

LSD1 inhibition improves efficacy of adoptive T cell therapy by enhancing CD8+ T cell responsiveness.

The lysine-specific histone demethylase 1A (LSD1) has been described to play a role in antitumor immunity; however, the role of LSD1 in shaping CD8+ T cell (CTL) differentiation and function is not understood. Here, we showed that pharmacological inhibition of LSD1 (LSD1i) in CTL elicited phenotypic and functional alterations of the CTL that led to robust antitumor immunity in the context of adoptive T cell therapy (ACT). In addition, the combination of anti-PDL1 therapy with LSD1i-based ACT resulted in a complete tumor eradication and long-lasting tumor-free survival. This study demonstrated that LSD1i together with anti-PDL1 therapy complement each others deficiencies and produce a better tumor response in a melanoma model, in which both immune and epigenetic therapy alone have shown limited efficacy. Collectively, these results set the translational potential of modulating LSD1 to improve antitumoral responses generated by ACT and anti-PDL1 therapy, which provide a strong rationale for a combination trial of LSD1i and immunotherapy.

immunology↗

bioRxiv2023

A fluorescent reporter model for the visualization and characterization of TDC

TDC are hematopoietic cells that combine dendritic cell (DC) and conventional T cell markers and functional properties. They were identified in secondary lymphoid organs (SLOs) of naive mice as cells expressing CD11c, major histocompatibility molecule (MHC)-II, and the T cell receptor (TCR) {beta} chain. Despite thorough characterization as to their potential functional properties, a physiological role for TDC remains to be determined. Unfortunately, using CD11c as a marker for TDC has the caveat of its upregulation on different cells, including T cells, upon activation. Therefore, a more specific marker is needed to further investigate TDC functions in peripheral organs in different pathological settings. Here we took advantage of Zbtb46-GFP reporter mice to explore the frequency and localization of TDC in peripheral tissues at steady state and upon viral infection. RNA sequencing analysis confirmed that TDC identified with this reporter model have a gene signature that is distinct from conventional T cells and DC. In addition, frequency and total numbers of TDC in the SLOs recapitulated those found using CD11c as a marker. This reporter model allowed for identification of TDC in situ not only in SLOs but also in the liver and lung of naive mice. Interestingly, we found that TDC numbers in the SLOs increased upon viral infection, suggesting that TDC might play a role during viral infections. In conclusion, we propose a visualization strategy that might shed light on the physiological role of TDC in several pathological contexts, including infection and cancer.

immunology↗

bioRxiv2018

Adaptor protein Bbc1 regulates localization of Wsp1 and Vrp1 during endocytic actin patch assembly

Arp2/3 complex-nucleated branched actin networks provide the force necessary for endocytosis. The Arp2/3 complex is activated by Nucleation Promoting Factors (NPFs) including the Schizosaccharomyces pombe proteins WASp Wsp1 and myosin-1 Myo1. There are >40 known yeast endocytic proteins with distinct spatial and temporal localizations and functions; however, it is still unclear how these proteins work together to drive endocytosis. We used quantitative live cell imaging to determine the function of the uncharacterized S. pombe protein Bbc1. We discovered Myo1 interacts with and recruits Bbc1 to sites of endocytosis. Bbc1 competes with verprolin Vrp1 for Myo1 binding, thus releasing Vrp1 and its binding partner Wsp1 from Myo1. Normally Myo1 remains at the base of the endocytic invagination and Vrp1-Wsp1 internalize with the endocytic vesicle; however, in the absence of Bbc1, a portion of Vrp1-Wsp1 remains with Myo1 at the base of the invagination and endocytic invaginations are twice as long. We propose that Bbc1 disrupts a transient Myo1-Vrp1-Wsp1 interaction and limits Arp2/3 complex-nucleation of actin branches at the plasma membrane.

cell biology↗