To characterize the T cells involved in the pathogenesis of cerebral malaria (CM) induced by infection with Plasmodium berghei ANKA clone 1.49L (PbA 1.49L), the occurrence of the disease was assessed in mice lacking T cells of either the alphabeta or gammadelta lineage (TCRalphabeta(-/-) or TCRgammadelta(-/-)). TCRgammadelta(-/-) mice were susceptible to CM, whereas all TCRalphabeta(-/-) mice were resistant, suggesting that T cells of the alphabeta lineage are important in the genesis of CM. The repertoire of TCR V(beta) segment gene expression was examined by flow cytometry in B10.D2 mice, a strain highly susceptible to CM induced by infection with PbA 1.49L. In these mice, CM was associated with an increase of T cells bearing the V(beta)8.1, 2 segments in the peripheral blood lymphocytes. Most V(beta)8.1, 2(+) T cells from peripheral blood lymphocytes of the mice that developed CM belonged to the CD8 subset, and exhibited the CD69(+), CD44(high) and CD62L(low) phenotype surface markers. The link between the increase in V(beta)8.1, 2(+) T cells and the neuropathological consequences of PbA infection was strengthened by the observation that the occurrence of CM was significantly reduced in mice treated with KJ16 antibodies against the V(beta)8.1 and V(beta)8.2 chains, and in mice rendered deficient in V(beta)8.1(+) T cells by a mouse mammary tumor virus superantigen.

To obtain insight into the mechanisms that contribute to the pathogenesis of Plasmodium infections, we developed an improved rodent model that mimics human malaria closely by inducing cerebral malaria (CM) through sporozoite infection. We used this model to carry out a detailed study on isolated T cells recruited from the brains of mice during the development of CM. We compared several aspects of the immune response related to the experimental model of Plasmodium berghei ANKA infection induced by sporozoites in C57BL/6 mice and those related to a blood-stage infection. Our data show that in both models, oligoclonal TCRV␤4 ؉ , TCRV␤6 ؉ , TCRV␤8.1 ؉ , and TCRV␤11 ؉ major histocompatibility complex class I-restricted CD8 T cells were present in the brains of CM ؉ mice. These CD8 ؉ T cells display an activated phenotype, do not undergo apoptosis, secrete gamma interferon or tumor necrosis factor alpha, and are associated with the development of the neurological syndrome.Cerebral malaria (CM) continues to contribute to the deaths of more than two million people every year in areas of endemic infection (World Health Organization, 1998, http://www .who.int/inf-fs/en/fact094.html). Although the physiopathology of Plasmodium infection has been extensively investigated, we still know relatively little about the precise mechanisms that contribute to its pathogenesis, in particular during CM. Two main factors have been implicated: (i) the sequestration of Plasmodium falciparum-parasitized red blood cells (8,27,35,37) and leukocytes (33, 36, 38) within brain vessels and (ii) the involvement of T cells activated by Plasmodium antigens (29, 41). These two main mechanisms act together under the control of mediators of the inflammatory responses released during the infection such as tumor necrosis factor alpha (TNF-␣) and gamma interferon (IFN-␥) (13,14,15,21,22,24,25). The up regulation of adhesion molecules such as CD36, intercellular cell adhesion molecule 1 (ICAM-1), and thrombospondin, which lead to the adherence of infected erythrocytes and leukocytes to endothelial cells of the brain microvessels, is a common feature of the physiological events that occur during CM (4, 7, 15, 39).Host CD4 ϩ and CD8 ϩ T cells are involved in the development of fatal murine CM, as demonstrated by depletion of these cells with anti-CD4 or anti-CD8 monoclonal antibodies (MAb) and by using mice that are genetically deficient in the expression of either CD4 or CD8 (2,5,12,17,18,30,42). This suggests that the immunopathological process that occurs during CM involves both CD4 ϩ and CD8 ϩ T-cell subsets. However, the way in which CD4 ϩ and CD8 ϩ cells contribute to the development of pathogenicity during fatal CM remains to be elucidated.The purpose of this study, therefore, was to develop an alternative model for CM, using sporozoites of P. berghei ANKA strain clone 1. 49L to initiate the infection in order to compare the pathogenic T-cell responses that occur during sporozoite-and blood-stage-induced infection in mice with CM. Such responses wer...

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Cerebral malaria (CM) is one of the severe complications of Plasmodium infection. In murine models of CM, Tαβ cells have been implicated in the neuropathogenesis. To obtain insights into the TCRB repertoire during CM, we used high throughput CDR3 spectratyping and set up new methods and software tools to analyze data. We compared PBL and spleen repertoires of mice infected with Plasmodium berghei ANKA that developed CM (CM+) or not (CM−) to evidence modifications of the TCRB repertoire associated with neuropathology. Using distinct statistical multivariate methods, the PBL repertoires of CM+ mice were found to be specifically altered. This alteration is partly due to recurrently expanded T cell clones. Strikingly, alteration of the PBL repertoire can be used to distinguish between CM+ and CM−. This study provides the first ex vivo demonstration of modifications of Tαβ cell compartment during CM. Finally, our original approach for deciphering lymphocyte repertoires can be transposed to various pathological conditions.