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However, in endemic regions, individuals can acquire \u2018clinical immunity\u2019 to malaria, characterized by a decrease in severe malaria episodes and an increase of asymptomatic <jats:italic>Plasmodium\u00a0falciparum<\/jats:italic> infections. Recently, it has been reported that tolerance to \u2018clinical malaria\u2019 and reduced disease severity correlates with a decrease in the numbers of circulating V\u03b39V\u03b42 T cells, the major subset of \u03b3\u03b4 T cells in the human peripheral blood. This is particularly interesting as this population typically undergoes dramatic expansions during acute <jats:italic>Plasmodium<\/jats:italic> infections and was previously shown to play antiparasitic functions. Thus, regulated \u03b3\u03b4 T\u2010cell responses may be critical to balance immune protection with severe pathology, particularly as both seem to rely on the same pro\u2010inflammatory cytokines, most notably TNF and IFN\u2010\u03b3. This has been clearly demonstrated in mouse models of experimental cerebral malaria (ECM) based on <jats:italic>Plasmodium\u00a0berghei<\/jats:italic> ANKA infection. Furthermore, our recent studies suggest that the natural course of <jats:italic>Plasmodium<\/jats:italic> infection, mimicked in mice through mosquito bite or sporozoite inoculation, includes a major pathogenic component in ECM that depends on \u03b3\u03b4 T cells and IFN\u2010\u03b3 production in the asymptomatic liver stage, where parasite virulence is seemingly set and determines pathology in the subsequent blood stage. Here, we discuss these and other recent advances in our understanding of the complex\u2014protective versus pathogenic\u2014functions of \u03b3\u03b4 T cells in malaria.<\/jats:p>","DOI":"10.1111\/febs.15494","type":"journal-article","created":{"date-parts":[[2020,7,25]],"date-time":"2020-07-25T01:55:26Z","timestamp":1595642126000},"page":"1118-1129","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["\u03b3\u03b4 T cells in malaria: a double\u2010edged sword"],"prefix":"10.1111","volume":"288","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5338-2768","authenticated-orcid":false,"given":"Ana","family":"Pamplona","sequence":"first","affiliation":[{"name":"Instituto de Medicina Molecular Jo\u00e3o Lobo Antunes Faculdade de Medicina Universidade de Lisboa 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