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A population of CD4^hiCD38^hi T cells correlates with disease severity in patients with acute malaria.

ABSTRACT: Objective: CD4⁺ T cells are critical mediators of immunity to Plasmodium spp. infection, but their characteristics during malarial episodes and immunopathology in naturally infected adults are poorly defined. Flow cytometric analysis of PBMCs from patients with either P. falciparum or P. knowlesi malaria revealed a pronounced population of CD4⁺ T cells co-expressing very high levels of CD4 and CD38 we have termed CD4^hiCD38^hi T cells. We set out to gain insight into the function of these novel cells.

Methods: CD4⁺ T cells from 18 patients with P. falciparum or P. knowlesi malaria were assessed by flow cytometry and sorted into populations of CD4^hiCD38^hi or CD4^norm T cells. Gene expression in the sorted populations was assessed by qPCR and NanoString.

Results: CD4^hiCD38^hi T cells expressed high levels of CD4 mRNA and canonical type 1 regulatory T-cell (TR1) genes including IL10, IFNG, LAG3 and HAVCR2 (TIM3), and other genes with relevance to cell migration and immunomodulation. These cells increased in proportion to malaria disease severity and were absent after parasite clearance with antimalarials.

Conclusion: In naturally infected adults with acute malaria, a prominent population of type 1 regulatory T cells arises that can be defined by high co-expression of CD4 and CD38 (CD4^hiCD38^hi) and that correlates with disease severity in patients with falciparum malaria. This study provides fundamental insights into T-cell biology, including the first evidence that CD4 expression is modulated at the mRNA level. These findings have important implications for understanding the balance between immunity and immunopathology during malaria.

SUBMITTER: Apte SH

PROVIDER: S-EPMC7684974 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A population of CD4hiCD38hi T cells correlates with disease severity in patients with acute malaria.

Apte Simon H SH Minigo Gabriela G Groves Penny L PL Spargo Jessie C JC Plebanski Magdalena M Grigg Mathew J MJ Kenangalem Enny E Burel Julie G JG Loughland Jessica R JR Flanagan Katie L KL Piera Kim A KA William Timothy T Price Ric N RN Woodberry Tonia T Barber Bridget E BE Anstey Nicholas M NM Doolan Denise L DL

Clinical & translational immunology 20201124 11

<h4>Objective</h4>CD4+ T cells are critical mediators of immunity to Plasmodium spp. infection, but their characteristics during malarial episodes and immunopathology in naturally infected adults are poorly defined. Flow cytometric analysis of PBMCs from patients with either P. falciparum or P. knowlesi malaria revealed a pronounced population of CD4+ T cells co-expressing very high levels of CD4 and CD38 we have termed CD4hiCD38hi ...[more]

PMID: 33282291

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Project description:BackgroundRegulatory T cells are known to play a key role to counter balance the protective immune response and immune mediated pathology. However, the role of naturally occurring regulatory cells CD4+CD25+Foxp3+ in malaria infection during the disease pathogenesis is controversial. Beside this, ICOS molecule has been shown to be involved in the development and function of regulatory T cell enhance IL-10 production. Therefore, possible involvement of the ICOS dependent regulatory CD4+ICOS+Foxp3+ T cells in resistance/susceptibility during malaria parasite is explored in this study.Methods5 × 105 red blood cells infected with non-lethal and lethal parasites were inoculated in female Balb/c mice by intra-peritoneal injection. Infected or uninfected mice were sacrificed at early (3rd day post infection) and later stage (10th day post infection) of infection. Harvested cells were analysed by using flow cytometer and serum cytokine by Bioplex assay.ResultsThin blood films show that percentages of parasitaemia increases with disease progression in infections with the lethal malaria parasite and mice eventually die by day 14th post-infection. Whereas in case of non-lethal malaria parasite, parasitaemia goes down by 7th day post infection and gets cleared within 13th day. The number of CD4+ ICOS+ T cells increases in lethal infection with disease progression. Surprisingly, in non-lethal parasite, ICOS expression decreases after day 7th post infection as parasitaemia goes down. The frequency of CD4+ICOS+FoxP3+ Tregs was significantly higher in lethal parasitic infection as compared to the non-lethal parasite. The level of IL-12 cytokine was remarkably higher in non-lethal infection compared to the lethal infection. In contrast, the level of IL-10 cytokines was higher in lethal parasite infection compared to the non-lethal parasite.ConclusionTaken together, these data suggest that lethal parasite induce immunosuppressive environment, protecting from host immune responses and help the parasite to survive whereas non-lethal parasite leads to low frequencies of Treg cells seldom impede immune response that allow the parasite to get self-resolved.

Dataset Information

A population of CD4^hiCD38^hi T cells correlates with disease severity in patients with acute malaria.

Publications

A population of CD4<sup>hi</sup>CD38<sup>hi</sup> T cells correlates with disease severity in patients with acute malaria.

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