The Journal of Experimental Medicine
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Published 1 April 2002. doi:10.1084/jem.20011174
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© Rockefeller University Press, 0022-1007/2002/4/881/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 7, April 1, 2002 881-892

Original Article

 The Mechanism and Significance of Deletion of Parasite-specific CD4+ T Cells in Malaria Infection

Huji Xu1, Jiraprapa Wipasa1, Huaru Yan1, Ming Zeng1, Morris O. Makobongo1, Fred D. Finkelman2,3, Anne Kelso1 and Michael F. Good1

1 The Cooperative Research Centre for Vaccine Technology, The Queensland Institute of Medical Research, Queensland 4029, Australia
2 Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267
3 Cincinnati Veterans Administration, Medical Center, Cincinnati, OH 45220

Address correspondence to Michael F. Good, The Queensland Institute of Medical Research, The Bancroft Centre, P.O. Royal Brisbane Hospital, Queensland 4029, Australia. Phone: 61-7-3362-0266; Fax: 61-7-3362-0110; E-mail: michaelG{at}qimr.edu.au

It is thought that both helper and effector functions of CD4+ T cells contribute to protective immunity to blood stage malaria infection. However, malaria infection does not induce long-term immunity and its mechanisms are not defined. In this study, we show that protective parasite-specific CD4+ T cells were depleted after infection with both lethal and nonlethal species of rodent Plasmodium. It is further shown that the depletion is confined to parasite-specific T cells because (a) ovalbumin (OVA)-specific CD4+ T cells are not depleted after either malaria infection or direct OVA antigen challenge, and (b) the depletion of parasite-specific T cells during infection does not kill bystander OVA-specific T cells. A significant consequence of the depletion of malaria parasite–specific CD4+ T cells is impaired immunity, demonstrated in mice that were less able to control parasitemia after depletion of transferred parasite-specific T cells. Using tumor necrosis factor (TNF)-RI knockout– and Fas-deficient mice, we demonstrate that the depletion of parasite-specific CD4+ T cells is not via TNF or Fas pathways. However, in vivo administration of anti–interferon (IFN)-{gamma} antibody blocks depletion, suggesting that IFN-{gamma} is involved in the process. Taken together, these data suggest that long-term immunity to malaria infection may be affected by an IFN-{gamma}–mediated depletion of parasite-specific CD4+ T cells during infection. This study provides further insight into the nature of immunity to malaria and may have a significant impact on approaches taken to develop a malaria vaccine.

Key Words: Plasmodium • apoptosis • cell-mediated immunity • immune evasion • IFN-{gamma}


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