Biology subjects

Firmino-Cruz, L.

Publications and source records attributed to Firmino-Cruz, L..

3 recordsLinked to original sources

bioRxiv2025

Lymphatic constraint of germinal centers optimizes protective antibody responses

Immunization strategies are central to pathogen control, where efficacy relies on antigen uptake, distribution, persistence, and inflammatory context. We recently demonstrated that dermal lymphatic capillaries regulate antigen presentation in lymph nodes (LN) by restraining fluid and virion transport following vaccinia virus (VACV) infection by skin scarification. Concurrently, a perifollicular, LN lymphangiogenic response encapsulates expanding B cell follicles. Given the important role of antigen transport and uptake on humoral immunity, we tested the hypothesis that lymphatic remodeling in the skin and LNs regulates germinal center (GC)-dependent antibody responses during infection. Using a model of lymphatic-specific VEGFR2 inhibition, we found that inhibiting viral-induced lymphatic remodeling in skin and LNs prompted significant GC expansion but paradoxically decreases protective VACV-specific class-switched antibodies. While the larger GC responses appeared structurally normal, they failed to support a proliferative burst consistent with clonal selection. Mathematical modeling revealed that this disconnect between GC size and function arises from impaired productive T follicular cell interactions in larger GC volumes and consistent with this finding, the optimal GC size was evolutionarily conserved across diverse mammals. Finally, we found that the presence of virus in the LN initiates these changes in GC function, inhibits LN lymphangiogenesis, increases B cell follicle size, and reduces selection efficiency. Therefore, protecting LN lymphatic vessels from virus-induced interferons rescues perifollicular lymphatic growth and follicle size, indicating that LN lymphangiogenesis directly constrains the follicular response. In summary, this study underscores the central role of lymphatic remodeling in compartmentalizing antigen and inflammatory signals to optimize GC fitness and protective antibody responses.

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↗

bioRxiv2019

Protection induced by anti-PD-1 and anti-PD-L1 treatment in Leishmania amazonensis-infected BALB/c mice

Leishmaniasis is a neglected disease, for which current treatment presents numerous issues. Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The roles of the programmed death-1 (PD-1) receptor on lymphocytes and its ligand (PD-L1) on antigen-presenting cells have been well studied in tumor and other infection models; but little is known about their roles in non-healing cutaneous leishmaniasis. Our previous report of L. amazonensis-induced PD-L1 expression on dendritic cells, in combination with decreased IFN-{gamma} production by CD4+ T cells in C57BL/6 mice, led to a hypothesis that the formation of the PD-1/PD-L1 complex contributes to down-modulation of immune responses, especially T cell suppression, enabling parasite survival and persistence. In this study, we tested the therapeutic potential of anti-PD-1 and anti-PD-L1 monoclonal antibodies (MoAbs) against a non-healing L. amazonensis infection in BALB/c mice. We observed that L. amazonensis induced PD-1 expression on both CD4+ and CD8+ T cells, and that anti-PD-1 and anti-PD-L1 treatment significantly increased IFN-{gamma}-producing CD4+ and CD8+ T cells, respectively. Compared with infection controls, mice that received treatment with anti-PD-1 and anti-PD-L1, but not anti-PD-L2, displayed bigger lesions with significantly lower parasite loads. Treatment did not affect anti-Leishmania antibody or IL-10 production, but anti-PD-1 treatment reduced both IL-4 and TGF-{beta} production. Together, our results highlight the therapeutic potential of an anti-PD-1-based treatment in promoting the reinvigoration of T cells for the control of parasite burden.

immunology↗