The regulation of CD4⁺ T cells during malaria

Malaria is a major global health problem. Despite decades of research, there is still no effective vaccine to prevent disease in the majority of people living in malaria-endemic regions. Additionally, drug treatment options are continually threatened by the emergence of drug-resistant parasites. Immune responses generated against Plasmodium 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-endemic areas indicate the rapid development of immunoregulatory pathways in response to Plasmodium infection. These "imprinted" 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-mediated protection against disease. A major target for and mediator of the immunoregulatory pathways established during malaria are CD4⁺ 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-parasitic antibodies. In this review, we describe mechanisms of CD4⁺ T cell activation during malaria and discuss the immunoregulatory mechanisms that develop to dampen their anti-parasitic and pathological functions. We also offer some ideas about how host-directed approaches might be applied to modulate CD4⁺ T cell functions to improve vaccine responses and enhance development of natural immunity.