Biology subjects

Silva-Santos, B.

Publications and source records attributed to Silva-Santos, B..

5 recordsLinked to original sources

bioRxiv2025

BATF3 controls the homeostatic maintenance and function of innate-like γδ T cells

{gamma}{delta} T cells compose an evolutionarily conserved lineage of lymphocytes, with both adaptive- and innate-like characteristics, contributing to tissue homeostasis, immune surveillance, and rapid responses to stress and infection. While their functional diversity and tissue-specific roles are tightly regulated by transcriptional networks, the underlying molecular mechanisms remain incompletely understood. The transcription factor basic leucine zipper ATF-like transcription factor 3 (BATF3) plays a central role in the development of conventional type 1 dendritic cells (cDC1s). Here, we unveil BATF3 as a critical cell-intrinsic regulator of the homeostasis, functional specialization, and tissue distribution of {gamma}{delta} T cells. Batf3-deficient mice display an altered composition of {gamma}{delta} T cell subsets, with a marked decrease in the numbers of innate-like {gamma}{delta} T cells across multiple organs when compared to their wild-type counterparts, independently of cDC1s. Loss of BATF3 impacts not only cell survival but also IL-17 production after {gamma}{delta} T cells complete their thymic development. Mechanistically, Batf3-deficient innate-like {gamma}{delta} T cells exhibit transcriptional changes that disrupt pathways governing actin cytoskeleton remodelling, immunological synapse organization and cellular identity. Notably, Batf3-deficient mice present decreased survival in a viral infection model highly dependent on innate-like {gamma}{delta} T cells. Together, our findings uncover a previously unrecognized BATF3-dependent pathway that controls {gamma}{delta} T cell morphology and function, profoundly impacting their biology.

immunology↗

bioRxiv2025

Dissection of the microRNA transcriptomes of CD4+ T cell subsets in autoimmune inflammation identifies novel regulators of disease pathogenesis

MicroRNAs (miRNAs) are key regulators of CD4+ T cell differentiation, but how they contribute to the course of an autoimmune disease in vivo remains poorly studied. Given the known roles in autoimmunity of pro-inflammatory T helper 1 (Th)1 and Th17 cells, and anti-inflammatory Foxp3+ regulatory cells, we established a triple reporter mouse for Ifng, Il17 and Foxp3, and subjected it to experimental autoimmune encephalomyelitis (EAE) to characterize the miRNomes of the corresponding CD4+ T cell subsets. We identified 110 miRNAs differentially expressed between the pro-inflammatory (Th1 and Th17 cells) and the Treg cell subsets. Among these, we found novel functions for miR-122-5p and miR-1247 as regulators of Th17 cell proliferation and Th1 cell differentiation, thus impacting the course or severity of EAE, respectively. Importantly, their expression patterns suggest miR-122-5p and miR-1247 act as peripheral brakes to CD4+ T cell pathogenicity that are subverted in the inflamed central nervous system.

immunology↗

bioRxiv2024

IL-17A/IFN-γ producing γ δ T cell functional dichotomy impacts cutaneous leishmaniasis in mice

{gamma}{delta} T cells are innate-like lymphocytes with pleiotropic roles in immune responses to pathogens, often ascribed to their IL-17A-producing or IFN-{gamma}-producing {gamma}{delta} T cell subsets. Here we investigated the impact of this functional dichotomy on cutaneous leishmaniasis, a set of neglected diseases caused by parasites of the Leishmania genus. We demonstrate that in Sv129 mice susceptible to Leishmania amazonensis, V{gamma}4+ {gamma}{delta} T cells are the main source of IL-17A. Furthermore, in type 1 interferon receptor-deficient (A129) mice presenting increased susceptibility to infection, there is a higher frequency of IL-17A-producing {gamma}{delta} T cells when compared to wild-type mice. Mechanistically, we demonstrate that lipophosphoglycan (LPG) of L. amazonensis induces IL-17A-producing {gamma}{delta} T cells. Importantly, C57Bl/6 mice deficient in {gamma}{delta} T cells or in IL-17 receptor (IL-17RA) show reduced lesion sizes, consistent with a pathogenic role of IL-17A-producing {gamma}{delta} T cells in cutaneous leishmaniasis. Conversely, the adoptive transfer of FACS-sorted {gamma}{delta} T cells led to an accumulation of IFN-{gamma}-producing {gamma}{delta} T cells in various susceptible strains of mice which associated with control of lesion development. These data demonstrate a pathophysiological dichotomy in which IL-17A-producing {gamma}{delta} T cells promote pathogenesis, whereas IFN-{gamma}-producing {gamma}{delta} T cells display therapeutic potential in cutaneous leishmaniasis.

immunology↗

bioRxiv2022

Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in Acute Myeloid Leukemia

Chimeric Antigen Receptor (CAR)-T cells have emerged as a breakthrough treatment for relapse/refractory (r/r) hematological tumors, showing impressive complete remission rates in B-cell malignancies. However, around 50% of the patients relapse before 1-year post-treatment. T-cell "fitness" is critical to prolong the persistence and activity of the adoptively transferred product. Allogeneic T cells from healthy donors are less dysfunctional or exhausted than autologous patient-derived T cells, enabling a very attractive and cost-effective "off-the-shelf" therapy option. In this context, Delta One T cells (DOTs), a recently described cellular product based on MHC/HLA-independent V{delta}1+ {gamma}{delta} T cells generated from the peripheral blood of healthy donors, represent a robust platform of allogeneic effector T cells. Here we generated and pre-clinically validated 4-1BB-based CAR-DOTs directed against the IL-3 chain receptor (CD123), a target antigen widely expressed on acute myeloid leukemia (AML) blasts. CD123CAR-DOTs showed vigorous, superior to control DOTs, cytotoxicity against AML cell lines and primary samples both in vitro and in vivo. Continuous administration of IL-15 supported the long-term persistence of a single-dose CD123CAR-DOTs in patient-derived xenograft models, sustaining their anti-leukemic efficacy as demonstrated in a re-challenge assay in vivo. Our results provide proof-of-concept for an allogeneic next-generation therapy based on CD123CAR-DOTs for r/r AML patients. KEY POINTS- CD123CAR-DOTs exert specific and robust cytotoxicity in vitro and anti-leukemic activity in vivo against AML cell lines and primary cells. - CD123CAR-DOTs show IL-15-dependent long-term persistence in vivo and vigorous anti-leukemic activity upon re-challenge.

immunology↗

bioRxiv2021

Maternal γδ T Cells Shape Offspring Pulmonary Type-2 Immunity In A Microbiota-Dependent Manner

Immune system development is greatly influenced by vertically transferred cues. However, beyond antibody-producing B cells, little is known about the role of other cell subsets of the maternal immune system in regulating offspring immunity. We reasoned {gamma}{delta} T cells to be attractive candidates based on their tissue distribution pattern: abundant in the skin, mammary glands and female reproductive tract. Here we found that mice born from {gamma}{delta} T cell-deficient (TCR{delta}-/-) dams display, early after birth, a pulmonary milieu selectively enriched in type-2 cytokines such as IL-33, IL-4, IL-5, and IL-13, and type-2-polarized immune cells, when compared to the progeny of {gamma}{delta} T cell-sufficient dams. In addition, upon helminth infection, mice born from TCR{delta}-/- dams sustained an increased type-2 inflammatory response. Critically, this was independent of the genotype of the pups. Despite similar levels of circulating antibodies in mothers and progeny, the intestinal microbiota in the offspring of TCR{delta}-/- and TCR{delta}+/- dams harbored distinct bacterial communities acquired during birth and fostering. These differences were accompanied by changes in the intestinal short-chain fatty acids (SCFA) profile. Importantly, antibiotic treatment abrogated the differences observed in the pulmonary milieu, and exogenous SCFA supplementation suppressed first-breath- and infection-induced inflammation. In summary, maternal {gamma}{delta} T cells control the establishment of a neonatal gut-lung axis by conditioning the postnatal microbial colonization of the off-spring and bacterial-derived metabolite availability; ultimately impacting on the development of pulmonary type-2 immunity in the offspring.

immunology↗