Plasmodium vivax infection changes the peripheral immunoregulatory network: CD4 T follicular cells and B cells

Regulatory and effector cell responses to Plasmodium vivax, the most common human malaria parasite outside Africa, remain understudied in naturally infected populations. Here, we describe peripheral CD4(+) T- and B-cell populations during and shortly after an uncomplicated P. vivax infection in 38 continuously exposed adult Amazonians. Consistent with previous observations, we found an increased frequency in CD4(+)CD45RA(-)CD25(+)FoxP3(+) T regulatory cells that express the inhibitory molecule CTLA-4 during the acute infection, with a sustained expansion of CD21(-)CD27(-) atypical memory cells within the CD19(+) B-cell compartment. Both Th1- and Th2-type subsets of CXCR5(+)ICOS(hi)PD-1(+) circulating T follicular helper (cTfh) cells, which are thought to contribute to antibody production, were induced during P. vivax infection, with a positive correlation between overall cTfh cell frequency and IgG antibody titers to the P. vivax blood-stage antigen MSP1(19). We identified significant changes in cell populations that had not been described in human malaria, such as an increased frequency of CTLA-4(+) T follicular regulatory cells that antagonize Tfh cells, and a decreased frequency of circulating CD24(hi)CD27(+) B regulatory cells in response to acute infection. In conclusion, we disclose a complex immunoregulatory network that is critical to understand how naturally acquired immunity develops in P. vivax malaria.