Reduced Plasmodium Parasite Burden Associates with CD38+ CD4+ T Cells Displaying Cytolytic Potential and Impaired IFN-γ Production.
Using a unique resource of samples from a controlled human malaria infection (CHMI) study, we identified a novel population of CD4+ T cells whose frequency in the peripheral blood was inversely correlated with parasite burden following P. falciparum infection. These CD4+ T cells expressed the multifunctional ectoenzyme CD38 and had unique features that distinguished them from other CD4+ T cells. Specifically, their phenotype was associated with proliferation, activation and cytotoxic potential as well as significantly impaired production of IFN-γ and other cytokines and reduced basal levels of activated STAT1. A CD38+ CD4+ T cell population with similar features was identified in healthy uninfected individuals, at lower frequency. CD38+ CD4+ T cells could be generated in vitro from CD38- CD4+ T cells after antigenic or mitogenic stimulation. This is the first report of a population of CD38+ CD4+ T cells with a cytotoxic phenotype and markedly impaired IFN-γ capacity in humans. The expansion of this CD38+ CD4+ T population following infection and its significant association with reduced blood-stage parasite burden is consistent with an important functional role for these cells in protective immunity to malaria in humans. Their ubiquitous presence in humans suggests that they may have a broad role in host-pathogen defense.



ClinicalTrials.gov clinical trial numbers ACTRN12612000814875, ACTRN12613000565741 and ACTRN12613001040752.
Molecular Vaccinology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.|The University of Queensland, School of Medicine, Brisbane, Australia.
Julie G
JG
Burel
Molecular Vaccinology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Simon H
SH
Apte
Molecular Vaccinology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Penny L
PL
Groves
Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
Kerenaftali
K
Klein
Clinical Tropical Medicine Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
James S
JS
McCarthy
Molecular Vaccinology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.|The University of Queensland, School of Medicine, Brisbane, Australia.|Centre for Biosecurity and Tropical Infectious Diseases, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
Denise L
DL
Doolan
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000328:Adult; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D003602:Cytotoxicity, Immunologic; D064368:Healthy Volunteers; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation; D016778:Malaria, Falciparum / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D018512:Parasitemia / Q000276:immunology / Q000473:pathology; D010963:Plasmodium falciparum / Q000276:immunology*
D008562:Membrane Glycoproteins; D007371:Interferon-gamma; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1
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