Biology subjects

Rivera, F.

Publications and source records attributed to Rivera, F..

3 recordsLinked to original sources

bioRxiv2025

Tissue-specific improvements in CD4+ T cell responses after treatment for visceral leishmaniasis.

Visceral leishmaniasis (VL) is a life-threatening parasitic disease that requires robust CD4+ T cell-mediated immunity for parasite control. However, the heterogeneity and transcriptional dynamics of CD4+ T cell responses in VL remain poorly defined. In this study, we use a model of experimental VL with tissue-specific immunity and single-cell RNA sequencing to provide a high-resolution assessment of CD4+ T cell responses. Our analysis reveals the complexity of CD4+ T cell differentiation in VL, identifying distinct Th1 subsets with transcriptional heterogeneity that may reflect functional specialisation. Despite minimal transcriptional differences between splenic and hepatic CD4+ T cells, we identified shifts in subset composition, including the emergence of a stem-like CD4+ T cell population in the spleen, which was suppressed by the transcription factor Bhlhe40. Bhlhe40 deficiency skewed CD4+ T cell differentiation, impairing Th1 responses while promoting Tr1 cells, resulting in defective parasite control in the liver. Additionally, AmBisome treatment induced a profound transcriptional shift in CD4+ T cells, leading to the maintenance of stem-like CD4+ T cells in the spleen and the expansion of tissue resident memory-like cells in the liver. These findings uncover key regulatory mechanisms that shape CD4+ T cell differentiation in VL and provide insights into how immune-modulatory strategies could enhance long-term immunity.

immunology↗

bioRxiv2023

Profiling the neuroimmune cascade in 3xTg mice exposed to successive mild traumatic brain injuries

Repetitive mild traumatic brain injuries (rmTBI) sustained within a window of vulnerability can result in long term cognitive deficits, depression, and eventual neurodegeneration associated with tau pathology, amyloid beta (A{beta}) plaques, gliosis, and neuronal and functional loss. However, we have limited understanding of how successive injuries acutely affect the brain to result in these devastating long-term consequences. In the current study, we addressed the question of how repeated injuries affect the brain in the acute phase of injury (<24hr) by exposing the 3xTg-AD mouse model of tau and A{beta} pathology to successive (1x, 3x, 5x) once-daily weight drop closed-head injuries and quantifying immune markers, pathological markers, and transcriptional profiles at 30min, 4hr, and 24hr after each injury. We used young adult mice (2-4 months old) to model the effects of rmTBI relevant to young adult athletes, and in the absence of significant tau and A{beta} pathology. Importantly, we identified pronounced sexual dimorphism, with females eliciting more differentially expressed proteins after injury compared to males. Specifically, females showed: 1) a single injury caused a decrease in neuron-enriched genes inversely correlated with inflammatory protein expression as well as an increase in AD-related genes within 24hr, 2) each injury significantly increased expression of a group of cortical cytokines (IL-1, IL-1{beta}, IL-2, IL-9, IL-13, IL-17, KC) and MAPK phospho-proteins (phospho-Atf2, phospho-Mek1), several of which were co-labeled with neurons and correlated with phospho-tau, and 3) repetitive injury caused increased expression of genes associated with astrocyte reactivity and immune function. Collectively our data suggest that neurons respond to a single injury within 24h, while other cell types including astrocytes transition to inflammatory phenotypes within days of repetitive injury.

neuroscience↗

bioRxiv2022

STING activation promotes autologous type I interferon-dependent development of type 1 regulatory T cells during malaria

The development of highly effective malaria vaccines and improving drug treatment protocols to boost anti-parasitic immunity is critical for malaria elimination. However, these efforts are hampered by parasite-specific immunoregulatory networks that are rapidly established following exposure to malaria parasites. Here, we identify stimulator of interferon genes (STING) as a critical mediator of type I interferon production by CD4+ T cells during blood-stage Plasmodium falciparum infection. STING activation by cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) stimulated IFNB gene transcription that promoted development of IL-10 and IFN{gamma} co-producing CD4+ T (type I regulatory; Tr1) cells. CD4+ T cell sensitivity to STING phosphorylation increased in healthy volunteers following P. falciparum infection, particularly in Tr1 cells. Finally, we found the JAK1/2 inhibitor ruxolitinib modulated this innate signalling axis in CD4+ T cells to increase parasite-specific Th1 and diminish Tr1 cell responses. These findings identify STING as a critical mediator of Tr1 cell development during malaria.

immunology↗