The mechanism and significance of deletion of parasite-specific CD4(+) T cells in malaria infection.
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.
Xu
Huji
H
The Cooperative Research Centre for Vaccine Technology, The Queensland Institute of Medical Research, Queensland 4029, Australia.
Wipasa
Jiraprapa
J
Yan
Huaru
H
Zeng
Ming
M
Makobongo
Morris O
MO
Finkelman
Fred D
FD
Kelso
Anne
A
Good
Michael F
MF
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000469:parasitology*; D002460:Cell Line; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D010961:Plasmodium / Q000145:classification / Q000276:immunology*; D010962:Plasmodium berghei / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
D015415:Biomarkers; D018124:Receptors, Tumor Necrosis Factor