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Multifunctional, TNF-α and IFN-γ-Secreting CD4 and CD8 T Cells and CD8^High T Cells Are Associated With the Cure of Human Visceral Leishmaniasis.

ABSTRACT: Visceral leishmaniasis (VL) is a chronic and often fatal disease caused by protozoans of the genus Leishmania that affects millions of people worldwide. Patients with symptomatic VL have an impaired anti-Leishmania-specific CD4⁺ T-cell response, which is reversed after clinical cure. In contrast, the quality of the CD4⁺ and CD8⁺ T-cell responses involved in resistance and/or cure of VL relies on the capability of these cells to activate polyfunctional and memory responses, which are associated with the simultaneous production of three cytokines: IFN-γ, IL-2, and TNF-α. Models for the development of CD4 and CD8 T-cell quality in memory and protection to leishmaniasis have been described previously. We aimed to assess the functionality of the T cells involved in the recovery of the immune suppression throughout the VL treatment. Therefore, we cultured peripheral blood mononuclear cells (PBMCs) from VL patients and healthy controls in vitro with soluble Leishmania antigen (SLA). Cell surface markers and intracellular cytokine production were determined on days 7, 14, 21, 30, 60, 90, and 180 after the beginning of chemotherapy. We observed that the frequencies of CD4⁺TNF-α⁺IFN-γ⁺ and the multifunctional CD4⁺IL-2⁺TNF-α⁺IFN-γ⁺, together with CD4⁺TNF-α⁺ and CD4⁺IFN-γ⁺ T cells, increased throughout and at the end of the treatment, respectively. In addition, enhanced frequencies of CD8⁺IL-2⁺TNF-α⁺IFN-γ⁺ and CD8⁺TNF-α⁺IFN-γ T cells were also relevant in the healing process. Noteworthy, the frequencies of the CD4⁺ and CD8 central-memory T cells, which produce IL-2, TNF-α, and IFN-γ and ensure the memory response against parasite reinfection, are significantly enhanced in cured patients. In addition, the subset of the non-functional CD8^Low population is predominant in VL untreated patients and decreases along the chemotherapy treatment. In contrast, a CD8^High subset increased towards the cure. Furthermore, the cure due to treatment with meglumine antimoniate or with liposomal amphotericin B was associated with the recovery of the T-cell immune responses. We described the evolution and participation of functional T cells during the treatment of patients with VL. Our results disclosed that the clinical improvement of patients is significantly associated with the participation of the CD4⁺ and CD8⁺ cytokine-secreting T cells.

SUBMITTER: Rodrigues LS

PROVIDER: S-EPMC8581227 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Multifunctional, TNF-α and IFN-γ-Secreting CD4 and CD8 T Cells and CD8High T Cells Are Associated With the Cure of Human Visceral Leishmaniasis.

Rodrigues Lorranny Santana LS Barreto Aline Silva AS Bomfim Lays Gisele Santos LGS Gomes Marcos Couto MC Ferreira Nathalia Luisa Carlos NLC da Cruz Geydson Silveira GS Magalhães Lucas Sousa LS de Jesus Amélia Ribeiro AR Palatnik-de-Sousa Clarisa B CB Corrêa Cristiane Bani CB de Almeida Roque Pacheco RP

Frontiers in immunology 20211028

Visceral leishmaniasis (VL) is a chronic and often fatal disease caused by protozoans of the genus Leishmania that affects millions of people worldwide. Patients with symptomatic VL have an impaired anti-Leishmania-specific CD4+ T-cell response, which is reversed after clinical cure. In contrast, the quality of the CD4+ and CD8+ T-cell responses involved in resistance and/or cure of VL relies on the capability of these cells to activate polyfunction ...[more]

PMID: 34777391

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Project description:IntroductionIn VL, a proinflammatory phenotype is typically associated with enhanced phagocytosis and a Th1 mediated immune response resulting in infection control. In contrast, an anti-inflammatory phenotype, associated with a predominant regulatory response, typically enables intracellular multiplication of Leishmania parasites and disease progression.MethodsTo investigate the impact of chemotherapy on Th2 and Th17 immune responses in patients with visceral leishmaniasis (VL), we assessed all combinations of intracellular expression of IFN-γ, IL-10, IL-4 and IL-17 in the CD4+ and CD8+ T cell populations of peripheral blood mononuclear cell (PBMC) samples from patients, after antigenic stimulation with Leishmania lysate, throughout treatment and follow-up. As increases in spleen and liver sizes and decreases in hematocrit, hemogloblin, erythrocytes, monocytes, leukocytes and platelets levels are strongly related to the disease, we studied the correlations between the frequencies of T cells producing the afore mentioned cytokines, individually and in combination, and these variables, as markers of disease or cure.ResultsWe found that the frequency of IFN-γ-producingCD4+ T cells increased until the end of chemotherapy with Glucantime® or AmBisome ®, while IL-10, IL-4 and IL-17-producing CD4+ T cells peaked on day 7 following the start of treatment. Although the frequency of CD4+IL-17+ cells decreased during treatment an increase was observed after clinical cure. The frequency of CD4+ T cells producing only IFN-γ or IL-17 correlated with blood monocytes levels. Frequencies of double-producers of IFN-γ and IL-10 or IL-4 correlated positively with eosinophils and platelets levels. Together, this suggest that IFN-γ drives the immune response towards Th1 at cure. In contrast, and associated with disease or Th2 response, the frequency of CD4+ IL-10+ cells correlated positively with spleen sizes and negatively with circulating monocyte levels, while the frequency of CD4+ producing both IL-4 and IL-10 correlated negatively with platelets levels. The frequency of CD8+ single-producers of IFN-γ increased from day 21 to 90 while that of single-producers of IL-10 peaked on day 7, of IL-4 on day 30 and of IL-17, on day 180. IFN-γ expression in CD8+ single- and double-producers of cytokines was indicative of an immune response associated with cure. In contrast, frequencies of CD8+ double-producers of IL-4 and IL-10, IL-4 and IL-17 and IL-10 and IL-17 and producers of three and four cytokines, were associated with disease and were low after the cure. Frequencies of CD8+ T cells producing IFN-γ alone or with IL-17 were positively correlated with platelets levels. In contrast, as markers of disease: 1) frequencies of single producers of IL-10 correlated negatively with leukocytes levels, 2) frequencies of double producers of IL-4 and IL-10 correlated negatively with platelet, leukocyte, lymphocyte and circulating monocyte levels, 3) frequencies of triple-producers of IFN-γ, IL-4 and IL-10 correlated negatively with platelet, leukocyte and neutrophil levels and 4) frequencies of producers of IFN-γ, IL-4, IL-10 and IL-17 simultaneously correlated positively with spleen size, and negatively with leukocyte and neutrophil levels.DiscussionOur results confirmed that the clinical improvement of VL patients correlates with the decrease of an IL-4 and IL-10 CD4+Th2 response, the recovery of CD4+ Th1 and Th17 responses and the frequency of CD8+ single-producers of IFN-γ and double producers of IFN-γ and IL-17.

Project description:BackgroundMetastatic castration-resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programmed necrosis ligand 1 (PD-L1) directly binds to PD-1 on the surface of T cells in the drain lineage lymph nodes or neutralizes administered PD-L1 antibodies, resulting in poor response to anti-PD-L1 therapy in mCRPC.Materials and methodsWestern blotting and immunofluorescence were performed to compare PD-L1 levels in exosomes derived from different prostate cancer cells. PC3 cells were subcutaneously injected into nude mice, and then ELISA assay was used to detect human specific PD-L1 in exosomes purified from mouse serum. The function of CD8+ T cells was detected by T cell mediated tumor cell killing assay and FACS analysis. A subcutaneous xenograft model was established using mouse prostate cancer cell RM1, exosomes with or without PD-L1 were injected every 3 days, and then tumor size and weight were analyzed to evaluate the effect of exosomal PD-L1.ResultsHerein, we found that exosomal-PD-L1 was taken up by tumor cells expressing low levels of PD-L1, thereby protecting them from T-cell killing. Higher levels of PD-L1 were detected in exosomes derived from the highly malignant prostate cancer PC3 and DU145 cell lines. Moreover, exosomal PD-L1 was taken up by the PD-L1-low-expressing LNCaP cell line and inhibited the killing function of CD8-T cells on tumor cells. The growth rate of RM1-derived subcutaneous tumors was decreased after knockdown of PD-L1 in tumor cells, whereas the growth rate recovered following exosomal PD-L1 tail vein injection. Furthermore, in the serum of mice with PCa subcutaneous tumors, PD-L1 was mainly present on exosomes.ConclusionIn summary, tumor cells share PD-L1 synergistically against T cells through exosomes. Inhibition of exosome secretion or prevention of PD-L1 sorting into exosomes may improve the therapeutic response of prostate tumors to anti-PD-L1 therapy.

Dataset Information

Multifunctional, TNF-α and IFN-γ-Secreting CD4 and CD8 T Cells and CD8^High T Cells Are Associated With the Cure of Human Visceral Leishmaniasis.

Publications

Multifunctional, TNF-α and IFN-γ-Secreting CD4 and CD8 T Cells and CD8<sup>High</sup> T Cells Are Associated With the Cure of Human Visceral <i>Leishmania</i>sis.

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