Leishmania donovani skews the CD56+ Natural Killer T cell response during human visceral leishmaniasis

Kumari, Shipra; Jamal, Fauzia; Shivam, Pushkar; Thakur, Ajit Kumar; Kumar, Manish; Bimal, Sanjiva; Das, Vidya Nand Rabi; Pandey, Krishna; Narayan, Shyam; Gupta, Anil Kumar; Das, Pradeep; Singh, Shubhankar Kumar

doi:10.1016/j.cyto.2015.01.011

Cited by 16 publications

(11 citation statements)

References 50 publications

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“…It is possible that the population of unconventional CD8 dim T cells are NKT-like cells expressing low levels of CD8α (61). However, our data do not support this hypothesis, since we did not observe a significant difference in CD56 mRNA or protein expression between CD8 bright and CD8 dim T cells (Supplemental Figure 2, C and F, and data not shown).…”

Section: Consistent With Our Findings Are Reports That Cd8contrasting

confidence: 56%

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Falanga¹,

Frascoli²,

Kaymaz³

et al. 2017

JCI Insight

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Cellular and humoral constituents of the immune system differ significantly between children and adults, yet very little is known about the impact of early-life pathogen exposure on this immunologic transition. We examined CD4+ and CD8+ T cell subsets defined by CCR7 and CD45RA expression in two longitudinal pediatric cohorts experiencing divergent levels of pathogen burden. Using multiparameter flow cytometry, along with serological, cytokine, and transcriptomic data, we show that cumulative pathogen burden promotes the development of atypical CD8dim T cells with an innate-like profile (Granzyme Bhi, IFNγlow, TNFαlow, PLFZhi, ID2hi, IKZF2hi) in contrast to age-matched children residing in a low pathogen-exposure area who display a more conventional CD8bright profile (IFNγ+, TNFα+, CCL4+). Furthermore, these unconventional T cells had stunted proliferation, distinct transcriptional programs, and impaired T cell receptor signaling and were enriched in hallmark TNFα, NF-κB, and IL-6 gene signaling pathways, reminiscent of NK cells and type-1 innate lymphoid cells. Our findings suggest that these unconventional CD8dim T cells arise in a very particular immunological context and may provide a deeper understanding of the heterogeneity in human immune responses

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Section: Consistent With Our Findings Are Reports That Cd8contrasting

confidence: 56%

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Falanga¹,

Frascoli²,

Kaymaz³

et al. 2017

JCI Insight

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“…A recent study about NKT cells in visceral leishmaniasis (VL) showed that patients with active disease had lower frequencies of CD4 + NKT and CD8 + NKT subsets, compared with HI. After the end of therapy, patients with VL kept low frequency of CD4 + NKT subset, while the CD8 + NKT subset levels returned to normal, thereby associating CD8 + NKT subset with a protective role in VL . We observed a lower frequency of DP NKT cells in patients with active disease, which was re‐established to healthy subject's levels with therapy and after healing, suggesting a protective role of this subset in CL.…”

Section: Discussionmentioning

confidence: 57%

Cytotoxic cell involvement in human cutaneous leishmaniasis: assessments in active disease, under therapy and after clinical cure

Cunha

Ferraz

Pimentel

et al. 2016

Parasite Immunology

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Cutaneous leishmaniasis (CL) is an important public health issue worldwide. The control of Leishmania infection depends on cellular immune mechanisms, and the inflammatory response may contribute to pathogenesis. A beneficial role of CD8(+) T lymphocytes has been proposed; nevertheless, other studies suggest a cytotoxic role of CD8(+) T lymphocytes involved in tissue damage, showing controversial role of these cells. The goal of the current study was to understand the immunopathology of CL and determine the profile of cytotoxic cells--such as CD4(+) T, natural killer and natural killer T cells--that might be involved in triggering immunological mechanisms, and may lead to cure or disease progression. The frequencies of cytotoxic cell populations in peripheral blood, obtained from patients with active disease, during treatment and after clinical healing, were assessed by flow cytometry. Cytotoxicity could not be related to a deleterious role in Leishmania braziliensis infection, as patients with active CL showed similar percentages of degranulation to healthy individuals (HI). Cured patients exhibited a lower percentage of degranulating cells, which may be due to a downregulation of the immune response. The understanding of the immunopathological mechanisms involved in CL and the commitment of cytotoxic cells enables improvements in therapeutic strategies.

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“…In humans, NKT cells play a role in several situations, for instance: showing either protective or pathogenic role against malaria; preventing autoimmunity; protecting against neoplasia, and having a direct pathogenic role against many opportunistic infections common in end-stage AIDS [42, 43]. In visceral leishmaniasis, NKT cells seem to have a dual behaviour, depending on their subset: CD4 + NKT cells show a pathogenic activity and tend to accumulate at the infection site, while CD8 + NKT cells may be protective when in contact with the target cells [44]. Our group has recently portrayed strong evidence about the involvement of CD8 + T and CD4 + T lymphocytes, NK and NKT cells (and their subsets) in the cytotoxic response analysing peripheral blood from CL patients before, during and after antimonial therapy.…”

Section: Discussionmentioning

confidence: 99%

CD3+CD4negCD8neg (double negative) T lymphocytes and NKT cells as the main cytotoxic-related-CD107a+ cells in lesions of cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis

et al. 2017

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BackgroundCutaneous leishmaniasis (CL) is caused by Leishmania (Viannia) braziliensis, which infects dermal macrophages and dendritic cells, causing an intense immune-mediated-tissue inflammation and a skin ulcer with elevated borders that can heal spontaneously or after antimonial therapy. The resolution of lesions depends on an adaptive immune response, and cytotoxic cells seem to have a fundamental role in this process. The aim of this study is to better understand the role of cytotoxicity mediated mechanisms that occur during the immune response in the CL lesion milieu, considering distinct cytotoxic-related CD107a+ cells, such as CD8+, CD4+, CD4neg CD8neg (double-negative, DN) and CD4+CD8+ (double-positive, DP) T lymphocytes, as well as NK and NKT cells.MethodsLesion derived cells were assessed for T cell subpopulations and NK cells, as well as CD107a expression by flow cytometry. In addition, cytometric bead array (CBA) was used to quantify cytokines and granzyme B concentrations in supernatants from macerated lesions.ResultsFlow cytometry analyses revealed that NKT cells are the major CD107a-expressing cell population committed to cytotoxicity in CL lesion, although we also observed high frequencies of CD4+ and DN T cells expressing CD107a. Analysing the pool of CD107a+-cell populations, we found a higher distribution of DN T cells (44%), followed by approximately 25% of NKT cells. Interestingly, NK and CD8+ T cells represented only 3 and 4% of the total-CD107a+-cell pool, respectively.ConclusionsThe cytotoxicity activity that occurs in the lesion milieu of CL patients seems to be dominated by DN T and NKT cells. These findings suggest the need for a reevaluation of the role of classical-cytotoxic NK and CD8+ T cells in the pathogenesis of CL, implicating an important role for other T cell subpopulations.

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Leishmania donovani skews the CD56+ Natural Killer T cell response during human visceral leishmaniasis

Cited by 16 publications

References 50 publications

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Cytotoxic cell involvement in human cutaneous leishmaniasis: assessments in active disease, under therapy and after clinical cure

CD3+CD4negCD8neg (double negative) T lymphocytes and NKT cells as the main cytotoxic-related-CD107a+ cells in lesions of cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis

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