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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:BackgroundThe global outbreak of coronavirus disease 2019 (COVID-19) has turned into a worldwide public health crisis and caused more than 100,000,000 severe cases. Progressive lymphopenia, especially in T cells, was a prominent clinical feature of severe COVID-19. Activated HLA-DR+CD38+ CD8+ T cells were enriched over a prolonged period from the lymphopenia patients who died from Ebola and influenza infection and in severe patients infected with SARS-CoV-2. However, the CD38+HLA-DR+ CD8+ T population was reported to play contradictory roles in SARS-CoV-2 infection.MethodsA total of 42 COVID-19 patients, including 32 mild or moderate and 10 severe or critical cases, who received care at Beijing Ditan Hospital were recruited into this retrospective study. Blood samples were first collected within 3 days of the hospital admission and once every 3-7 days during hospitalization. The longitudinal flow cytometric data were examined during hospitalization. Moreover, we evaluated serum levels of 45 cytokines/chemokines/growth factors and 14 soluble checkpoints using Luminex multiplex assay longitudinally.ResultsWe revealed that the HLA-DR+CD38+ CD8+ T population was heterogeneous, and could be divided into two subsets with distinct characteristics: HLA-DR+CD38dim and HLA-DR+CD38hi. We observed a persistent accumulation of HLA-DR+CD38hi CD8+ T cells in severe COVID-19 patients. These HLA-DR+CD38hi CD8+ T cells were in a state of overactivation and consequent dysregulation manifested by expression of multiple inhibitory and stimulatory checkpoints, higher apoptotic sensitivity, impaired killing potential, and more exhausted transcriptional regulation compared to HLA-DR+CD38dim CD8+ T cells. Moreover, the clinical and laboratory data supported that only HLA-DR+CD38hi CD8+ T cells were associated with systemic inflammation, tissue injury, and immune disorders of severe COVID-19 patients.ConclusionsOur findings indicated that HLA-DR+CD38hi CD8+ T cells were correlated with disease severity of COVID-19 rather than HLA-DR+CD38dim population.

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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