Supplementary Materials1. CXCR3? Tfh cell reactions may improve malaria vaccine effectiveness. Intro The mosquito-borne parasite causes an estimated 200 million instances of malaria and 600,000 deaths each year, mainly among African children (W.H.O., 2014). Several studies in malaria-endemic areas have shown that children generally have short-lived antibody reactions to illness, leaving them susceptible to repeated bouts of malaria (Portugal et al., 2013). Moreover, the most clinically advanced malaria vaccine candidate induces short-lived antibody reactions (Alonso et al., 2005; Riley and Stewart, 2013) and confers only partial, short-term safety against malaria in African children (Rts, 2014). The mechanisms underlying short-lived antibody response to both natural malaria illness and candidate malaria vaccines, particularly in African children, are poorly understooda essential knowledge space that hinders the development of a highly effective malaria vaccine (Crompton et al., 2014; Langhorne et GW843682X al., 2008). In general, it is well-established that long-lived, high-affinity antibody reactions, which are induced by many pathogens and vaccines after a single or few exposures (Amanna et al., 2007), depend on the generation of long-lived plasma cells (LLPCs) and memory space B cells (MBCs) within germinal centers (GC) of secondary lymphoid organs (Tarlinton and Good-Jacobson, 2013). In the GC, follicular helper T (Tfh) cells, which communicate high levels of CXCR5 (Breitfeld et al., 2000; Schaerli et al., 2000) and the transcription element Bcl6 (Johnston et al., 2009; Nurieva et al., 2009; Yu et al., 2009), provide essential support for the differentiation of na?ve B cells into isotype-switched, affinity-matured LLPCs and MBCs through their production of cytokines such as IL-4 and IL-21 and co-stimulatory molecules such as CD40L (Crotty, 2014). After providing help to B cells, GC Tfh cells may exit the GC, down-regulate Bcl6 and become memory CXCR5+CD4+ Tfh cells that recirculate in blood and then return to the GC upon antigen re-exposure (Hale et al., 2013; Kitano et al., 2011; Shulman et al., 2013), although it is not required that a Tfh cell progress through a GC Tfh state to become a memory space Tfh cell (He et al., 2013). Studies in healthy adults have shown that circulating memory space CXCR5+CD4+ Tfh cells resemble GC Tfh cells in their capacity to produce IL-21 and induce B cell differentiation (Chevalier et al., 2011; Ma and Deenick, 2014; Morita et al., 2011b). Although circulating Tfh cell subpopulations are varied (Schmitt and Ueno, 2013), recent work in healthy adults Mouse monoclonal to SCGB2A2 recognized circulating PD-1+CXCR3?CXCR5+ Tfh cells as the most closely related to bona fide GC Tfh cells by gene expression, cytokine profile and practical capacity (Locci et al., 2013). Whether these observations hold true in children is unknownan important knowledge gap given that children are the main target population for most vaccines, including candidate malaria vaccines. Furthermore, studies of Tfh cells in humans to date have been limited to healthy individuals following immunization (Bentebibel et al., 2013), or cross-sectional analyses of individuals with primary or acquired immunodeficiency (i.e., HIV) (Cubas et al., 2013), autoimmunity or various cancers (Ma and Deenick, 2014); whereas longitudinal studies of Tfh responses before, during and after an acute natural infection have not been published. Despite the crucial role of Tfh cells in humoral immunity, and the enormous disease burden of malaria worldwide, there are no published studies of Tfh cells in human malaria to date (Perez-Mazliah GW843682X and Langhorne, 2014). Notably, in mouse models of malaria, immunotherapy targeting Tfh cells through blockade of PD-L1 and LAG-3 augmented Tfh cell and GC B GW843682X cell frequencies, increased antibody levels and accelerated the clearance of blood-stage malaria parasites (Butler et al., 2011). Conversely, simultaneously activating OX40 and blocking PD-1 signaling revealed that excessive IFN- limits Tfh responses and humoral anti-immunity (Zander et al., 2015). Finally, it was recently reported that disruption of IL-21 signaling in mice affects T cell-B cell interactions and abrogates protective humoral immunity to malaria (Perez-Mazliah et al., 2015). Together, these reports identify pathways to potentially manipulate Tfh cells in humans to improve the efficacy of vaccines targeting malaria.