T cell suppression in the bone marrow of visceral leishmaniasis patients: impact of parasite load

Kumar, Prabin; Misra, Pragya; Thakur, C.P.; Saurabh, Abhinav; Rishi, Narayan; Mitra, Dipendra Kumar

doi:10.1111/cei.13074

Cited by 10 publications

(10 citation statements)

References 22 publications

(52 reference statements)

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“…In addition, regarding the regulatory CD4 T-cell response, Treg cells were found to accumulate in the bone marrow of symptomatic VL patients from India. These Treg lymphocytes expand in response to L. (L.) donovani antigens and produce IL-10, which inhibits the T-cell response (13,14). In agreement, the frequencies of CD4 + CD25 High and CD4 + Foxp3 + Treg cells were reduced in the peripheral blood mononuclear cell (PBMC) compartment of symptomatic subjects (15).…”

Section: Introductionmentioning

confidence: 81%

“…TNF-a is one of the main cytokines involved in protection against VL; however, at high levels, it can also cause tissue damage (38,39). On the other hand, the IFN-g-producing CD4 + T cells are considered one of the main functional cells during Leishmania infection (13,40). However, IFN-g promotes macrophage stimulation and inhibition of Th2 cells; thus, when its secretion increases, the patient immune response may be more effective against the parasite (35).…”

Section: Discussionmentioning

confidence: 99%

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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

et al. 2021

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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 CD8Low population is predominant in VL untreated patients and decreases along the chemotherapy treatment. In contrast, a CD8High 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.

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Section: Introductionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…This fact points out that not only residual HIV, but also Leishmania can be contributing to the severely impaired thymic function in VL/HIV patients. Previous studies have shown that Leishmania can affect T-cell progenitors in the bone marrow and the thymic microenvironment (46)(47)(48), which may also favor the deficient thymic output under conditions of VL. Additionally, as previously described, the parasite potentiates the immune activation degree (5,49), mainly in R-VL/HIV cases (13), which in turn may lead to thymic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Impaired Thymic Output Can Be Related to the Low Immune Reconstitution and T Cell Repertoire Disturbances in Relapsing Visceral Leishmaniasis Associated HIV/AIDS Patients

et al. 2020

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Silva-Freitas et al. Thymic Impairment in VL/HIV Patients Results: VL/HIV cases presented an altered mobilization profile (expansions or retractions) of the TCRVβ families when compared to HS independent of the follow-up phase (p < 0.05). TCRVβ repertoire on CD4 + T-cells was more homogeneous in the NR-VL/HIV cases, but heterogeneous on CD8 + T-cells, since different Vβ-families were mobilized. NR-VL/HIV had the inflammatory pattern reduced after 6 mpt. Importantly, VL/HIV patients showed number of TREC copies lower than controls during all follow-up. An increase of recent thymic emigrants was observed in NR-VL/HIV individuals at 10 mpt compared to R-patients (p < 0.01), who maintained lower TREC contents than the HIV controls. Conclusions: VL/HIV patients that maintain the thymic function, thus generating new T-cells, seem able to replenish the T lymphocyte compartment with effector cells, then enabling parasite control.

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“…Rather, some peptide pools induced a suppressive effect on IL-10 production. This anti-inflammatory cytokine has been involved in parasite persistence and disease establishment but also in controlling an excessive inflammatory response [15,18,90]. The immunomodulatory effect of some of our peptides may not be beneficial to the host, given the role of IL-10 in the regulation of exsessive IFN-γ responses [18].…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

Design of multi-epitope peptides containing HLA class-I and class-II-restricted epitopes derived from immunogenic Leishmania proteins, and evaluation of CD4+ and CD8+ T cell responses induced in cured cutaneous leishmaniasis subjects

et al. 2020

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Human leishmaniasis is a public health problem worldwide for which the development of a vaccine remains a challenge. T cell-mediated immune responses are crucial for protection. Peptide vaccines based on the identification of immunodominant T cell epitopes able to induce T cell specific immune responses constitute a promising strategy. Here, we report the identification of human leukocyte antigen class-I (HLA-I) and-II (HLA-II)-restricted multiepitope peptides from Leishmania proteins that we have previously described as vaccine candidates. Promastigote Surface Antigen (PSA), LmlRAB (L. major large RAB GTPase) and Histone (H2B) were screened, in silico, for T cell epitopes. 6 HLA-I and 5 HLA-IIrestricted multi-epitope peptides, able to bind to the most frequent HLA molecules, were designed and used as pools to stimulate PBMCs from individuals with healed cutaneous leishmaniasis. IFN-γ, IL-10, TNF-α and granzyme B (GrB) production was evaluated by ELISA/CBA. The frequency of IFN-γ-producing T cells was quantified by ELISpot. T cells secreting cytokines and memory T cells were analyzed by flow cytometry. 16 of 25 peptide pools containing HLA-I, HLA-II or HLA-I and-II peptides were able to induce specific and significant IFN-γ levels. No IL-10 was detected. 6 peptide pools were selected among those inducing the highest IFN-γ levels for further characterization. 3/6 pools were able to induce a significant increase of the percentages of CD4+IFN-γ+, CD8+IFN-γ+ and CD4+GrB+ T cells. The same pools also induced a significant increase of the percentages of bifunctional IFN-γ+/TNF-α+CD4+ and/or central memory T cells. We identified highly promiscuous HLA-I and-II restricted epitope combinations from H2B, PSA and LmlRAB proteins that stimulate both CD4+ and CD8+ T cell responses in recovered individuals. These multi-epitope peptides could be used as potential components of a polytope vaccine for human leishmaniasis.

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T cell suppression in the bone marrow of visceral leishmaniasis patients: impact of parasite load

Cited by 10 publications

References 22 publications

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

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

Impaired Thymic Output Can Be Related to the Low Immune Reconstitution and T Cell Repertoire Disturbances in Relapsing Visceral Leishmaniasis Associated HIV/AIDS Patients

Design of multi-epitope peptides containing HLA class-I and class-II-restricted epitopes derived from immunogenic Leishmania proteins, and evaluation of CD4+ and CD8+ T cell responses induced in cured cutaneous leishmaniasis subjects

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