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Despite decades of research, there is still no effective vaccine to prevent disease in the majority of people living in malaria\u2010endemic regions. Additionally, drug treatment options are continually threatened by the emergence of drug\u2010resistant parasites. Immune responses generated against <jats:italic>Plasmodium<\/jats:italic> parasites that cause malaria are generally not sufficient to prevent the establishment of infection and can even contribute to the development of disease, unless individuals have survived multiple infections. Research conducted in experimental models, controlled human malaria infection studies, and with malaria patients from disease\u2010endemic areas indicate the rapid development of immunoregulatory pathways in response to <jats:italic>Plasmodium<\/jats:italic> infection. These \u201cimprinted\u201d immune responses limit inflammation, and likely prevent progression to severe disease manifestations. However, they also cause slow acquisition of immunity and possibly hamper the development of vaccine\u2010mediated protection against disease. A major target for and mediator of the immunoregulatory pathways established during malaria are CD4<jats:sup>+<\/jats:sup> T cells that play critical roles in priming phagocytic cells to capture and kill malaria parasites, as well as helping B cells produce functional anti\u2010parasitic antibodies. In this review, we describe mechanisms of CD4<jats:sup>+<\/jats:sup> T cell activation during malaria and discuss the immunoregulatory mechanisms that develop to dampen their anti\u2010parasitic and pathological functions. We also offer some ideas about how host\u2010directed approaches might be applied to modulate CD4<jats:sup>+<\/jats:sup> T cell functions to improve vaccine responses and enhance development of natural immunity.<\/jats:p>","DOI":"10.1111\/imr.12804","type":"journal-article","created":{"date-parts":[[2019,11,1]],"date-time":"2019-11-01T12:57:03Z","timestamp":1572613023000},"page":"70-87","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["The regulation of CD4<sup>+<\/sup> T cells during malaria"],"prefix":"10.1111","volume":"293","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2338-1494","authenticated-orcid":false,"given":"Rajiv","family":"Kumar","sequence":"first","affiliation":[{"name":"Centre of Experimental Medicine and Surgery Institute of Medical Sciences Banaras Hindu University Varanasi UP India"},{"name":"Department of Medicine Institute of Medical Sciences Banaras Hindu University Varanasi UP 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