Biology subjects

dos Santos Dias, L.

Publications and source records attributed to dos Santos Dias, L..

4 recordsLinked to original sources

bioRxiv2026

Natural Killer Cell Granule Protein (NKG7) promotes the development of vaccine-induced anti-fungal Th1 cells

CD4+ T cells that produce IFN-{gamma} (T helper 1 [Th1] cells) chiefly mediate vaccine acquired resistance to fungal infections. However, the key regulators of the development of Th1 cells and acquired resistance to fungi are incompletely understood. Here, we report that Natural Killer Cell Granule Protein (NKG7) acts as an unappreciated regulator inducing anti-fungal Th1 cells to produce IFN-{gamma} and converting plastic Th17 cells into polyfunctional memory Th1 cells. Author summaryThe mechanisms of vaccine resistance to fungi are incompletely understood. We identified a regulator that promotes the development of proinflammatory immune lymphocytes and fosters the conversion of one population of lymphocytes into multi-functional cells that produce several proinflammatory soluble factors that efficiently combat infectious diseases.

immunology↗

bioRxiv2026

Combination adjuvants drive long lived plastic Th17 cells that convert to multi-functional Th1 cells and protect mice against fungal infection

Th1 cells are viewed as a cornerstone of immunity to fungi and other intracellular pathogens. Despite the widely accepted role of Th1 cells in antifungal resistance, the development of protective strategies harnessing them is stunted by a limited understanding of how best to promote their development. We and others have reported a requisite role for Th17 cells in resistance to fungi. We have long been puzzled about how to reconcile seminal roles for both Th1 and Th17 subsets. Here we report that Th17 cells convert into polyfunctional Th1 cells producing multiple cytokines, including IFN-{gamma}, TNF and GM-CSF when we used adjuvant formulations that include glucopyranosyl lipid adjuvant (GLA) to enhance antifungal immunity. GLA induced plastic Th17 cells that convert into polyfunctional Th1 memory cells.

immunology↗

bioRxiv2026

Selective JAK Inhibition Reveals Paradoxical and Hierarchical Control of interferon-γ-driven Autoimmunity in AIRE Deficiency

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by impaired central immune tolerance due to deficiency of the Autoimmune Regulator (AIRE) and is characterized by severe, multiorgan autoimmunity. We recently identified interferon-{gamma} (IFN-{gamma}) as a dominant driver of immunopathology in APECED and showed that treatment with the JAK1/2 inhibitor ruxolitinib ameliorates disease in both AIRE-deficient mice and patients. However, broad JAK inhibition is associated with clinically relevant toxicities, raising the question of whether selective targeting of individual JAK pathways can retain efficacy while sparing nonpathogenic immune programs. Here, we systematically evaluated the effects of selective JAK1, JAK2, and JAK3 inhibition in Aire-/- mice. Selective JAK1 and JAK2 inhibition reduced autoimmune tissue injury, suppressed IFN-{gamma} signaling, and decreased accumulation of pathogenic T cells, with JAK2 inhibition providing the most robust protection, comparable to ruxolitinib. In contrast, selective JAK3 inhibition decreased T cell accumulation, but paradoxically increased the proportion of IFN-{gamma}-producing T cells and did not significantly attenuate IFN-{gamma}-driven tissue inflammation. These findings reveal an unexpected uncoupling between lymphocyte burden and pathogenic cytokine bias and identify IFN-{gamma} signaling as hierarchically dominant over {gamma}c-dependent pathways in AIRE deficiency. Together, our data indicate that effective control of APECED-associated autoimmunity requires direct suppression of the IFN-{gamma}-JAK2 axis rather than generalized lymphocyte inhibition and suggest that selective JAK2 targeting may represent a rational strategy to preserve therapeutic efficacy while minimizing disruption of JAK1-and {gamma}c-dependent immune functions.

immunology↗

bioRxiv2025

Endoglucanase-2 (Eng2), a conserved immunodominant antigen in dimorphic fungi that elicits immunity and resistance during infection

Herein, we describe a conserved surface and cell wall protein, Endoglucanase 2 (Eng2), expressed on the etiological agents that cause the endemic systemic mycoses of North America - Blastomyces, Coccidioides and Histoplasma. We demonstrate that despite sequence variation of the protein across these related fungi, exposure to Eng2 vaccinates and protects inbred and humanized HLA-DR4 strains of mice against lethal experimental infections with these fungi by eliciting adaptive immunity mediated by CD4 T cells. We also show that CD4 T cell precursors against Eng2 are detectable in naive individuals and that patients who have recovered from these infections evince a memory and recall CD4 T cell response to Eng2 and its immunodominant epitopes that we have mapped. We create and catalogue new tools and information such as immunodominant peptide epitopes of Eng2 from each fungus recognized by inbred mice and human subjects and we engineer novel peptide-MHC II tetramers for tracking T cells in inbred and HLA-DR4 humanized mice that will be useful for those who study these infections in mice and humans. Lastly, because most patients demonstrate memory and recall responses against Eng2, our work oRers new tools for diagnosis of this collection of infectious diseases across North America.

immunology↗