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In their recent review article, published in Nature Reviews Immunology, Stevenson and Riley1 comment that, “The role of these [γδ T] cells in immunity to P. chabaudi and P. yoelii blood-stages does not seem to be crucial.” However, a review of the literature leads to a different conclusion: γδ T cells have an essential function in the T-cell-dependent cell-mediated immune response to blood-stage malaria parasites.
Mice rendered B-cell deficient by treatment with μ-specific antibody or gene knockout suppress acute Plasmodium chabaudi parasitaemia to low levels (usually less than 1%) with the same time course as control mice2,3,4, indicating that cell-mediated immunity can be activated early to control acute parasitaemia. In contrast to the ability of B-cell-deficient mice to control parasitaemia, B-cell-deficient mice that are depleted of γδ T cells by treatment with monoclonal antibody or double knockout (B-cell-deficient × T-cell receptor δ-chain-deficient) mice develop high levels (more than 10%) of unremitting parasitaemia5,6,7. This finding indicates that γδ T cells are essential for the cell-mediated immune response to experimental malaria. Depletion of CD4+ T cells by monoclonal antibody treatment in both B-cell-deficient and intact mice results in high levels of unremitting P. chabaudi parasitaemia and abrogates the clonal expansion of the γδ T-cell population during malaria8. Together, these results support our conclusion that γδ T cells are crucial for the T-cell-dependent cell-mediated immune response to experimental malaria.
In human malaria, γδ T cells are mainly activated during acute infection. Clinical studies indicate that the γδ T-cell population (both Vδ1 and Vδ2 subpopulations) increases during acute infection when the cell-mediated immune response is activated but not in individuals with many sequential infections with Plasmodium9. The in vitro expansion of the γδ T-cell population to Plasmodium falciparum antigens depends on CD4+ T cells, but this requirement can be replaced by exogeneous cytokines, such as interleukin-2 (IL-2), IL-4 and IL-15, that signal through the g-chain of the IL-2 receptor10. So, human γδ T cells also respond during P. falciparum malaria and are regulated by CD4+ αβ T cells, which are similar to the findings for experimental P. chabaudi malaria.
How do γδ T cells contribute to controlling the replication of blood-stage malarial parasites? Both human and mouse γδ T cells secrete interferon-γ and other crucial pro-inflammatory cytokines in response to stimulation with malarial antigens11,12. In addition, human γδ T-cell lines and clones isolated from the peripheral blood of malaria-naive individuals inhibit the replication of P. falciparum parasites in vitro, with both Vγ9- and Vδ1-expressing clones displaying activity12,13. The levels of soluble granzyme B are increased in the sera of patients infected with P. falciparum and cytotoxic αβ T cells and/or natural killer cells are thought to secrete this cytotoxic protein during malaria14. However, γδ T cells, which secrete granzymes on activation12, are also cytotoxic T cells and might also contribute to the increased soluble granzyme B levels in the plasma of P. falciparum-infected patients.
In conclusion, the literature cited above indicates that γδ T cells do function as an integral part of the cell-mediated immune response to Plasmodium infection and can have a crucial role in controlling parasite replication.
References
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van der Heyde, H., Weidanz, W. γδ T cells function in cell-mediated immunity to malaria. Nat Rev Immunol 4, 656 (2004). https://doi.org/10.1038/nri1311-c1
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DOI: https://doi.org/10.1038/nri1311-c1
