Follicular Helper T Cells are Essential for the Elimination of Plasmodium Infection

CD4+ follicular helper T (Tfh) cells have been shown to be critical for the activation of germinal center (GC) B-cell responses. Similar to other infections, Plasmodium infection activates both GC as well as non-GC B cell responses. Here, we sought to explore whether Tfh cells and GC B cells are required to eliminate a Plasmodium infection. A CD4 T cell-targeted deletion of the gene that encodes Bcl6, the master transcription factor for the Tfh program, resulted in complete disruption of the Tfh response to Plasmodium chabaudi in C57BL/6 mice and consequent disruption of GC responses and IgG responses and the inability to eliminate the otherwise self-resolving chronic P. chabaudi infection. On the other hand, and contrary to previous observations in immunization and viral infection models, Signaling Lymphocyte Activation Molecule (SLAM)-Associated Protein (SAP)-deficient mice were able to activate Tfh cells, GC B cells, and IgG responses to the parasite. This study demonstrates the critical role for Tfh cells in controlling this systemic infection, and highlights differences in the signals required to activate GC B cell responses to this complex parasite compared with those of protein immunizations and viral infections. Therefore, these data are highly pertinent for designing malaria vaccines able to activate broadly protective B-cell responses. •Chronic Plasmodium infection cannot be eliminated in the absence of Tfh cell responses.•SAP-deficient mice are able to activate GC Tfh and GC B-cell responses to Plasmodium infection.•There is a hierarchical requirement for the control of chronic Plasmodium infection following IL-21R>Tfh cells>SAP. Successful vaccines work through activation of protective B-cell responses. Malaria, caused by Plasmodium infection transmitted by mosquito bites, remains a global threat. Despite substantial efforts, a vaccine able to bring about high levels of protection from Plasmodium infection remains elusive. Here, using an experimental malaria model including natural mosquito transmission, we demonstrate that proper activation of follicular helper CD4+ T cells is essential for the control and eradication of chronic Plasmodium infection through protective B-cell responses. Thus, it is strongly advisable for novel vaccine efforts to monitor the robust activation of this important immune compartment.