Parasitology Research

, 105:281 | Cite as

CD4+ T cell response in early erythrocytic stage malaria: Plasmodium berghei infection in BALB/c and C57BL/6 mice

  • Akiko ShibuiEmail author
  • Nobumichi Hozumi
  • Chiharu Shiraishi
  • Yoshitaka Sato
  • Hajime Iida
  • Sumio Sugano
  • Junichi Watanabe
Short Communication


Plasmodium berghei ANKA causes lethal malaria in mice. It is well established that C57BL/6 mice die early with fulminant symptoms including convulsion, whereas BALB/c mice survive this phase and die later of anemia and prostration. Early death in C57BL/6 mice has been considered to result from the adverse effects of inflammatory cytokines. To elucidate the CD4+ T cell responses in early death due to severe malaria, the kinetics of CD4+ T cells were compared by analyzing cell surface markers and the production of cytokines and transcription factors. The results revealed that cytokine production by CD4+ T cells was induced as early as 5 days after infection and the maintenance of higher levels of IL-4 and IL-10 may be associated with the protection of BALB/c mice from early death. These results suggest that parasite control in the early phase of infection may be important for the development of an effective vaccine.


Malaria Treg Cell Severe Malaria Early Death Cerebral Malaria 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This work was supported in part by a Grant-in Aid for Young Researchers from the Ministry of Education and Science of Japan (50313846 to AS).


  1. Armah HB, Wilson NO, Sarfo BY, Powell MD, Bond VC, Anderson W, Adjei AA, Gyasi RK, Tettey Y, Wiredu EK, Tongren JE, Udhayakumar V, Stiles JK (2007) Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children. Malar J 6:147CrossRefPubMedGoogle Scholar
  2. Belkaid Y, Rouse BT (2005) Natural regulatory T cells in infectious disease. Nat Immunol 6:353–360CrossRefPubMedGoogle Scholar
  3. Cockburn IA, Zavala F (2007) T cell memory in malaria. Curr Opin Immunol 19:424–429CrossRefPubMedGoogle Scholar
  4. Cruz Cubas AB, Gentilini M, Monjour L (1994) Cytokines and T-cell response in malaria. Biomed Pharmacothr 48:27–33CrossRefGoogle Scholar
  5. Doolan DL, Martinez-Alier N (2006) Immune response to pre-erythrocytic stages of malaria parasites. Curr Mol Med 6(2):169–185CrossRefPubMedGoogle Scholar
  6. Ferrante A, Kumaratilake L, Rzepczyk CM, Dayer JM (1990) Killing of Plasmodium falciparum by cytokine activated effector cells (neutrophils and macrophages). Immunol Lett 25(1–3):179–187CrossRefPubMedGoogle Scholar
  7. Griffith JW, O’Connor C, Bernard K, Town T, Goldstein DR, Bucala R (2007) Toll-like receptor modulation of murine cerebral malaria is dependent on the genetic background of the host. J Infect Dis 196:1553–1564CrossRefPubMedGoogle Scholar
  8. Haque A, Echchannaoui H, Seguin R, Schwartzman J, Kasper LH, Haque S (2001) Cerebral malaria in mice: interleukin-2 treatment induces accumulation of γδ T cells in the brain and alters resistant mice to susceptible-like phenotype. Am J Pathol 158(1):163–172PubMedGoogle Scholar
  9. Hisaeda H, Maekawa Y, Iwakawa D, Okada H, Himeno K, Kishihara K, Tsukumo S, Yasumoto K (2004) Escape of malaria parasites from host immunity requires CD4+CD25+ regulatory T cells. Nat Med 10:29–30CrossRefPubMedGoogle Scholar
  10. Hoffman SL, Isenbarger D, Long GW, Sedgah M, Szarfman A, Mellouk S, Ballou WR (1990) T lymphocytes from mice immunized with irradiated sporozoites eliminate malaria from hepatocytes. Bull World Health Organ 68(Suppl):132–137PubMedGoogle Scholar
  11. de Kossodo S, Grau GE (1993) Profiles of cytokine production in relation with susceptibility to cerebral malaria. J Immunol 151(9):4811–4820PubMedGoogle Scholar
  12. Langhorne J (1994) The immune response to the blood stages of Plasmodium in animal models. Immunol Lett 41:99–102CrossRefPubMedGoogle Scholar
  13. Langhorne J, Albano FR, Hensmann M, Sannni L, Cadman E, Voisine C, Sponaas AM (2004) Dendritic cells, pro-inflammatory responses, and antigen presentation in a rodent malaria infection. Immunol Rev 201:35–47CrossRefPubMedGoogle Scholar
  14. Long TTA, Nakazawa S, Onizuka S, Huaman MC, Kanbara H (2003) Influence of CD4+CD25+ T cells on Plasmodium berghei NK65 infection in BALB/c mice. Int J Parasitol 33:175–183CrossRefPubMedGoogle Scholar
  15. Mackintosh CL, Beeson JG, Marsh K (2004) Clinical features and pathogenesis of severe malaria. Trends Parasitol 20(12):597–603CrossRefPubMedGoogle Scholar
  16. Nie CQ, Bernard NJ, Schofield BL, Hansen DS (2007) CD4+CD25+ regulatory T cells suppress CD4+ T-cell function and inhibit the development of Plasmodium berghei-specific Th1 responses involved in cerebral malaria pathogenesis. Infect Immun 75:2275–2282CrossRefPubMedGoogle Scholar
  17. Perlmann P, Perlmann H, Berzins K, Troye-Blomberg M (1998) Selected problems of malaria blood stage immunity. Tokai J Exp Clin Med 23:55–62PubMedGoogle Scholar
  18. Riley EM, Wahl S, Perkins DJ, Schofield L (2006) Regulating immunity to malaria. Parasite Immunol 28:35–49CrossRefPubMedGoogle Scholar
  19. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor a-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155(3):1151–1164PubMedGoogle Scholar
  20. Seixas E, Ostler D (2005) Plasmodium chabaudi chabaudi (AS): differential cellular responses to infection in resistant and susceptible mice. Exp Parasitol 110:394–405CrossRefPubMedGoogle Scholar
  21. Stephens R, Langhorne J (2006) Priming of CD4+ T cells and development of CD4+ T cell memory; lessons for malaria. Parasite Immunol 28:25–30CrossRefPubMedGoogle Scholar
  22. Stephens R, Albano FR, Quin S, Pascal BJ, Harrison V, Stockinger B, Kioussis D, Weltzien H, Langhorne J (2008) Malaria-specific transgenic CD4+ T cells protect immunodeficient mice from lethal infection and demonstrate requirement for a protective threshold of antibody production for parasite clearance. Blood 106:1676–1684CrossRefGoogle Scholar
  23. Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI (2005) The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature 434:214–217CrossRefPubMedGoogle Scholar
  24. Walther M, Tongren JE, Andrews L, Korbel D, King E, Fletcher H, Andersen RF, Bejon P, Thompson F, Dunachie SJ, Edele F, de Souza JB, Sinden RE, Gilbert SC, Riley EM, Hill AV (2005) Upregulation of TGF-b, FOXP3 and CD4+ regulatory T cells correlates with more rapid parasite growth in human malaria infection. Immunity 23(3):287–296CrossRefPubMedGoogle Scholar
  25. Weaver CT, Hatton RD, Mangan PR, Harrington LE (2007) IL-17 family cytokines and the expanding diversity of effector T cell lineage. Annu Rev Immunol 25:821–852CrossRefPubMedGoogle Scholar
  26. WHO (1992) World malaria situation 1990. World Health Stat Q 45:257–266Google Scholar
  27. Yanez DM, Manning DD, Cooley AJ, Weidanz WP, van der Heyde HC (1996) Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria. J Immunol 157(4):1620–1624PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Akiko Shibui
    • 1
    Email author
  • Nobumichi Hozumi
    • 1
  • Chiharu Shiraishi
    • 1
  • Yoshitaka Sato
    • 1
  • Hajime Iida
    • 1
  • Sumio Sugano
    • 2
  • Junichi Watanabe
    • 3
  1. 1.Research Institute for Biological SciencesTokyo University of ScienceNodaJapan
  2. 2.Department of Medical Genomics, Graduate School of Frontier SciencesThe University of TokyoKashiwaJapan
  3. 3.Department of Parasitology, Institute of Medical ScienceThe University of TokyoMinatokuJapan

Personalised recommendations