CD4 T cell responses to flaviviruses

Flaviviruses pose an increasing threat to global health with their potential to cause severe disease in millions of people. Protective and long-lived immunity is closely linked to the generation of CD4 T cells, which provide B cell help and support high affinity neutralizing antibody responses. Research performed during the last years revealed important new insights into the antigen specificities and diverse effector functions of CD4 T cell responses to flaviviruses. Moreover, the identification of mechanisms involved in the regulation of T cell specificity and function provides significant advances in our understanding of how durable protective immunity is established. Here, we summarize what is known about human CD4 T cell responses to flaviviruses, with a special emphasis on CD4 T cells that provide direct help to B cells producing neutralizing and protective antibodies. We review recent progress in the identification of epitope sites in the context of the atomic structures of flavivirus proteins and highlight specific influences that shape the human CD4 T cell response in the context of infection or vaccination. Finally, we discuss challenges facing vaccine efforts to generate appropriate CD4 T cell responses, as well as recent strategies to enhance T cell-mediated antibody responses.