Ageing dangerously; homing of senescent CD8 T cells in cutaneous Leishmaniasis

Milling, Simon

doi:10.1111/imm.13188

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…Some authors related that T cells expressing CD57 + were shown in high frequency on CL lesions caused by L. braziliensis [21]. Corroborated with our hypothesis, Milling S. showed that in infected tissues, CD8 + CD57 + T cells are responsible for the high cytotoxicity observed in CL skin lesions and higher damage capability compared to infiltrated NK cells expressing CD57 + [25]. In fact, we find the same profile of NK cells in DL patients with less capability compared to CD8 + CD57 + T cells in both DL and CL ulcers.…”

Section: Discussionsupporting

confidence: 80%

“…CD8 + T cells expressing GzB were found on CL and DL biopsies, showing their involvement in both clinical forms of the disease [ 24 ]. Recently, Milling S reported that senescent CD8 + T cells are apparently the most important cell population mediating the disease pathology observed in CL [ 25 ]. In the present study, we evaluated the participation of senescent CD8 + T cells in the pathogenesis of DL compared to CL on peripheral blood, biopsies, stimulated in vitro cultures, and performed co-culture functional assays.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis

Abreu,

Nascimento,

Bacellar

et al. 2024

Pathogens

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Disseminated leishmaniasis (DL) caused by L. braziliensis is characterized by the presence of 10 to more than 1000 lesions spread on the body. While protection against Leishmania is mediated by macrophages upon activation by IFN-γ produced by CD4+T cells, the pathology of disseminated leishmaniasis (DL) could be mediated by macrophages, NK, and CD8+T cells. Herein, we evaluate the participation of senescent CD8+T cells in the pathogenesis of DL. Methods: Peripheral blood mononuclear cells (PBMCs), biopsies, co-cultures of CD8+T cells with uninfected and infected macrophages (MØ), and PBMC cultures stimulated with soluble L. braziliensis antigen (SLA) for 72 h from patients with cutaneous leishmaniasis (CL) and DL were used to characterize senescent CD8+T cells. Statistical analysis was performed using the Mann–Whitney and Kruskal–Wallis tests, followed by Dunn’s. Results: Patients with DL have an increase in the frequency of circulating CD8+T cells that present a memory/senescent phenotype, while lesions from DL patients have an increase in the frequency of infiltrating CD8+T cells with a senescent/degranulation phenotype. In addition, after specific stimuli, DL patients’ circulating CD8+T with memory/senescent profile, showing degranulation characteristics, increased upon SLA stimuli, and those specific CD8+T cells from DL patients had an increased degranulation phenotype, causing more apoptosis of infected target cells. Conclusions: DL patients show a higher frequency of cytotoxic senescent CD8+T cells compared to CL patients, and that could promote the lysis of infected cells, although without parasite killing, releasing Leishmania to the extracellular compartment, contributing to the spread of parasites.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis

Abreu,

Nascimento,

Bacellar

et al. 2024

Pathogens

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“…Hematopoietic cells are the main cellular source of IFN-α, whereas fibroblasts are the main cellular source of IFN-β 25 . Initially, it was believed that only CD4 + T helper type 1 (Th1) lymphocytes, CD8 + cytotoxic T lymphocytes, and NK cells produce IFN-γ 26 , 27 .However, current evidence indicates that other cells such as B cells, natural killer T (NKT) cells and antigen-presenting cells (APCs) can also secrete IFN-γ 28 – 32 .…”

Section: Resultsmentioning

confidence: 99%

Interferon-γ in the tumor microenvironment promotes the expression of B7H4 in colorectal cancer cells, thereby inhibiting cytotoxic T cells

Jing,

Liu,

Zhou

et al. 2024

Sci Rep

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The bioactivity of interferon-γ (IFN-γ) in cancer cells in the tumor microenvironment (TME) is not well understood in the current immunotherapy era. We found that IFN-γ has an immunosuppressive effect on colorectal cancer (CRC) cells. The tumor volume in immunocompetent mice was significantly increased after subcutaneous implantation of murine CRC cells followed by IFN-γ stimulation, and RNA sequencing showed high expression of B7 homologous protein 4 (B7H4) in these tumors. B7H4 promotes CRC cell growth by inhibiting the release of granzyme B (GzmB) from CD8+ T cells and accelerating apoptosis in CD8+ T cells. Furthermore, interferon regulatory factor 1 (IRF1), which binds to the B7H4 promoter, is positively associated with IFN-γ stimulation-induced expression of B7H4. The clinical outcome of patients with CRC was negatively related to the high expression of B7H4 in cancer cells or low expression of CD8 in the microenvironment. Therefore, B7H4 is a biomarker of poor prognosis in CRC patients, and interference with the IFN-γ/IRF1/B7H4 axis might be a novel immunotherapeutic method to restore the cytotoxic killing of CRC cells.

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“…The low proportion of ML among young patients is well described in hospital- and field-based case series in Brazil and Bolivia 3 , 17 , 19 . The recurrence of the disease, affecting the mucosa during old age after the healing of cutaneous ulcers associated with CL, suggests that the immunosenescence phenomenon may be involved in this clinical phenotype 20 .…”

Section: Discussionmentioning

confidence: 99%

Factors associated with mucosal involvement in tegumentary leishmaniasis: a nation-based study using surveillance data from Brazil

Monachesi,

Gomes-Silva,

Carvalho-Costa

2023

Rev. Inst. Med. trop. S. Paulo

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This study aimed to assess the factors associated with mucosal leishmaniasis (ML) within the scope of tegumentary leishmaniasis (TL) cases reported in Brazil. Surveillance data were assessed, and comparisons were made between ML and cutaneous leishmaniasis (CL) cases. Additionally, ML incidence rates for municipalities were depicted through a geographic information system. From 2007 to 2017, 235,489 TL cases were reported, of which 235,232 were classified as follows: 14,204 (6%) were ML cases and 221,028 (94%) were CL cases. Multivariate analysis showed that the proportion of ML cases reached 16.8% among individuals >75 years (adjusted OR = 2.77; 95% CI = 2.41-3.19; p < 0.001), and ML was also more frequent among males (aOR = 1.28; 95% CI = 1.20-1.38; p < 0.001), HIV-positive patients (aOR = 2.15; 95% CI = 1.80-2.56; p < 0.001), patients residing in urban areas (aOR = 1.52; 95% CI = 1.43-1.62; p < 0.001), and imported cases (with respect to county) when compared to autochthonous cases (aOR = 1.84; 95% CI = 1.71-1.98; p < 0.001). A lower proportion of positive results in direct parasitological examinations was observed in ML cases (32.6% vs. 60.8%; p < 0.001). The leishmanin skin test results were more often positive in ML cases (41.7% vs. 25.9%; p < 0.001). In ML, compatible changes in histopathology were more frequent (14.6% vs. 3.9%; p < 0.001). A greater proportion of ML cases were treated with amphotericin B (6.9% vs. 0.9%; p < 0.001). The case-fatality rate was higher in ML (0.6% vs. 0.1%; p < 0.001). A higher incidence of ML was observed in a geographical band extending across the Amazon region from the southern Para State to the Acre State. ML exhibited varying frequencies within specific populations. The definition of predictable factors predisposing Leishmania-infected subjects to develop ML is important for defining strategies to mitigate the mucosal damage caused by leishmaniasis.

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Ageing dangerously; homing of senescent CD8 T cells in cutaneous Leishmaniasis

Cited by 9 publications

References 12 publications

The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis

The Role of Senescent CD8+T Cells in the Pathogenesis of Disseminated Leishmaniasis

Interferon-γ in the tumor microenvironment promotes the expression of B7H4 in colorectal cancer cells, thereby inhibiting cytotoxic T cells

Factors associated with mucosal involvement in tegumentary leishmaniasis: a nation-based study using surveillance data from Brazil

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