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T cell response in malaria pathogenesis: selective increase in T cells carrying the TCR V(beta)8 during experimental
M I Boubou1, A Collette, D Voegtlé
1INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires,CHU Pitié-Salpêtrière, 75643 Paris Cedex 13, France.
Abstract:
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.
Insights
Alphabeta T cells are crucial for cerebral malaria (CM) development. Research shows specific V(beta)8.1,2 T cells, particularly CD8+ cells, are elevated during CM and blocking them reduces disease severity.
Area of Science:
- Immunology
- Pathogenesis of Infectious Diseases
- Neuroscience
Background:
- Cerebral malaria (CM) is a severe complication of Plasmodium infection, but the specific T cell subsets involved remain incompletely understood.
- Understanding T cell roles is critical for developing targeted therapies against CM.
Purpose of the Study:
- To identify the T cell lineages and specific T cell receptor (TCR) V(beta) segments implicated in the pathogenesis of Plasmodium berghei ANKA (PbA)-induced cerebral malaria.
- To investigate the phenotype and functional relevance of these T cells in disease development.
Main Methods:
- Comparative analysis of disease susceptibility in mice lacking alphabeta or gammadelta T cell receptor (TCR) lineages (TCRalphabeta(-/-) or TCRgammadelta(-/-)).
- Flow cytometry to examine TCR V(beta) segment gene expression in peripheral blood lymphocytes of susceptible B10.D2 mice during PbA infection.
- Phenotypic characterization (CD69, CD44, CD62L) of implicated T cell subsets.
- Experimental blockade using antibodies (KJ16) against V(beta)8.1/8.2 chains and superantigen-mediated T cell depletion.
Main Results:
- TCRalphabeta(-/-) mice were resistant to CM, while TCRgammadelta(-/-) mice were susceptible, indicating a critical role for alphabeta T cells.
- CM development in B10.D2 mice was associated with an increased frequency of peripheral blood T cells expressing V(beta)8.1,2 segments.
- These V(beta)8.1,2(+) T cells were predominantly CD8+ and displayed an activated phenotype (CD69+, CD44high, CD62Llow).
- Treatment with anti-V(beta)8.1/8.2 antibodies or depletion of V(beta)8.1(+) T cells significantly reduced CM incidence.
Conclusions:
- Alphabeta T cells, specifically CD8+ T cells expressing V(beta)8.1,2 TCR segments, are key players in the pathogenesis of experimental cerebral malaria.
- Targeting these specific T cell populations may offer a therapeutic strategy for preventing or mitigating cerebral malaria.
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