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A population of CD4hiCD38hiT cells correlates with disease severity in patients with acute malaria


Apte, SH and Minigo, G and Groves, PL and Spargo, JC and Plebanski, M and Grigg, MJ and Kenangalem, E and Burel, JG and Loughland, JR and Flanagan, KL and Piera, KA and William, T and Price, RN and Woodberry, T and Barber, BE and Anstey, NM and Doolan, DL, A population of CD4hiCD38hiT cells correlates with disease severity in patients with acute malaria, Clinical and Translational Immunology, 9, (11) pp. 1-18. ISSN 2050-0068 (2020) [Refereed Article]

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Copyright 2020 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) License (

DOI: doi:10.1002/cti2.1209


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 CD4and CD38 we have termed CD4hiCD38hi 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 CD4hiCD38hi or CD4norm T cells. Gene expression in the sorted populations was assessed by qPCR and NanoString.

Results: CD4hiCD38hi 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 (CD4hiCD38hi) 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.

Item Details

Item Type:Refereed Article
Keywords:CD38, CD4 co‐receptor modulation, CD4+ T cells, malaria, regulatory T cells
Research Division:Biomedical and Clinical Sciences
Research Group:Clinical sciences
Research Field:Infectious diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Diagnosis of human diseases and conditions
UTAS Author:Flanagan, KL (Dr Katie Flanagan)
ID Code:151785
Year Published:2020
Web of Science® Times Cited:1
Deposited By:Medicine
Deposited On:2022-08-04
Last Modified:2022-10-05
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