, and Leishmania braziliensis infections as well as in humans and mice infected with Leishmania donovani, the causative agent of visceral leishmaniasis (Espitia et al., 2010;Bollig et al., 2012;Costa et al., 2015;Kong et al., 2017;Khatonier et al., 2018). IL-21 expression significantly and positively correlated with expression of IFN-γ and IL-27, but not FoxP3 or TGF-β, in human subjects with L. braziliensis cutaneous lesions (Costa et al., 2015). CD3 + T cells were the major source of IL-21 expression during visceral leishmaniasis in humans (Ansari et al., 2011). Further, recombinant human IL-21 could augment antigen-specific IL-10 production in a whole-blood assay (Ansari et al., 2011). However, an earlier report failed to establish a connection between the lack of IL-21R signaling and impaired T H1 -biased immunity against L. major infection (Frohlich et al., 2007). In this study, Il21r −/− mice mounted a strong T H1 immune response against L. major infection as evidenced by a higher percentage of antigen-specific IFN-γ-producing CD4 + T cells and these mice had comparable footpad swellings as compared with C57BL/6 controls (Frohlich et al., 2007). These findings suggest that the IL-21/IL-21R signaling axis was not required for host defense against L. major and that the absence of IL-21R signaling was not critical for the development of a T H1 -biased response against this intracellular protozoan parasite.
Host strain-specific susceptibility or resistant to infection is considered an important determinant of disease outcome in parasitic diseases (Araujo et al., 1976;Ruebush and Hanson, 1979;Ishii and Sano, 1989;Duleu et al., 2004). Varied susceptibility of C57BL/6 (resistant) and Balb/c (susceptible) strains to L. major, for example, represents a classical dichotomy as to how host's genetic background can contribute to disease outcome following leishmanial infections (Lohoff et al., 1989;Scott, 1991;Sommer et al., 1998;Barbi et al., 2008). Several mechanisms have been proposed as to why some mouse strains are more susceptible to a given parasite while others do not (von Stebut et al., 1998;Rosas et al., 2005;Nigg et al., 2007). These may include discrepancies in the magnitude of a particular immune pathway and/or the differential expression of immune compartments and/or immune effector molecules between mouse strains (von Stebut et al., 2000;Von Stebut et al., 2003;Hurdayal et al., 2013;Sassi et al., 2015). Analysis of the GC B cell response in the draining lymph nodes (dLNs) of C3HeB/FeJ and C57BL/6 mice (which develop healing and non-healing lesions, respectively) in a L. major/Leishmania amazonensis model of co-infection revealed that the inability of C57BL/6 mice to resolve leishmanial lesions correlated with reduced numbers of GC B cells and memory B cells and fewer parasite-specific antibody-producing cells as compared with the C3HeB/FeJ strain (Gibson-Corley et al., 2012). In this study, the differences in the local production of IL-21 or different expression levels of IL-21R did not explain the distinct clinical profiles observed between the two strains, since the two strains had comparable local production and expression of IL-21 and IL-21R, respectively (Gibson-Corley et al., 2012). These findings may suggest that varied clinical profiles in the mouse strains developing healing (C3HeB/FeJ) vs. nonhealing (C57BL/6) lesions can be mainly due to the mouse strain-dependent discrepancies in intrinsic T FH cell or B cell functional properties.
It is well-established that the IFN-regulatory factor (IRF) family of transcription factors are key players in T H differentiation; whereas IRF1 is crucial for T H1 differentiation (Lohoff et al., 1997;Lohoff and Mak, 2005), IRF4 is required for T H2 and T H17 cell differentiation (Brustle et al., 2007;Huber et al., 2008). Mice deficient for IRF4 (Irf4 −/− ) were characterized by their failure to form GCs in the draining popliteal lymph nodes in response to chronic L. major infection as well as their inability of dLN-derived T FH cells to optimally express and secrete IL-21 at both the mRNA and protein levels, respectively (Bollig et al., 2012). These observations may suggest an important role played by IRF4 in T FH cellsderived IL-21 expression in response to a chronic, intracellular parasitic pathogen.

Schistosomes
Several studies have demonstrated that IL-21 is induced at both the mRNA and protein levels during natural infections with several species of schistosomes in humans and in murine models of schistosomiasis (Milner et al., 2010;Bourke et al., 2013;Zhang Y. et al., 2016), as well as following vaccination with schistosome-derived peptides (Zhang et al., 2013Bourke et al., 2014;Fairfax et al., 2015). Ileal lamina propria lymphocytes-(LPLs) and axillary lymph node-derived T cells and non-T cell subsets from uninfected rhesus macaques (Macaca mulatta) secreted high levels of IL-21 in a recall assay in response to S. mansoni (Sm) egg antigen (SmEA) and worm antigen (SmWA) preparations ex vivo (Torben et al., 2017). Dendritic cell-specific adhesion molecule-3-grabbing non-integrin (DC-SIGN, CD209) controls the differentiation of T FH cells via IL-27 expression during infections with S. mansoni and the liver fluke, Fasciola hepatica (Gringhuis et al., 2014). Interestingly, the transcription factor, IFN-stimulated gene factor 3 (ISGF3) induces the expression of the IL-27 subunit p28 by primed DCs, and IL-27 produced by DCs is required for the differentiation of T FH cells and the subsequent IL-21 expression by T FH cells during infections with trematodes, including S. mansoni and F. hepatica (Gringhuis et al., 2014).
In contrast to potential roles played by the IL-21/IL-21R signaling axis in protective immunity during infection with trematodes, earlier studies demonstrated that the IL-21/IL-21R signaling pathway promotes the induction of tissue damage following Schistosoma spp. infections (Pesce et al., 2006). While parasite burdens were comparable between wild-type mice and mice lacking a functional IL-21/IL-21R signaling axis (Il21r −/− ), the lack of a functional IL-21/IL-21R signaling pathway in Il21r −/− mice infected with S. mansoni led to diminished T H2dependent immunopathology in those mice, as evidenced by attenuated formation of granulomatous inflammation and liver fibrosis (Pesce et al., 2006). Mechanistically, the impaired S. mansoni-induced granulomatous formation in Il21r −/− mice correlated with a significant impairment in both the tissue expression and the function of T H2 cytokines, including IL-4 and IL-13, required for the fibrotic tissue responses during S. mansoni infection (Pesce et al., 2006). Furthermore, IL-21 treatment of the bone marrow-derived macrophages (BMDM) promotes the expression of cognate receptors for IL-4 and IL-13 (IL-4Rα and IL-13Rα1) in macrophages, indicating that the augmentation of alternate macrophage activation can occur in an IL-21/IL-21R axis-dependent manner (Pesce et al., 2006).
It is known that the ICOS/ICOSL axis contributes to the T cell differentiation, T cell activation and its optimal functions (Hutloff et al., 1999;Dong et al., 2001). Mice deficient in either a functional ICOS or ICOSL (Icos −/− and Icosl −/− mice, respectively) had diminished levels of serum antibodies, defective antibody class switching and impaired GC formation and T H17 cell development (Dong et al., 2001;Nurieva et al., 2003). Consistent with the requirement of the ICOS/ICOSL signaling pathway in the development and the function of T H17 cells, Icosl −/− mice infected with Schistosoma japonicum showed decreased expression of T H17 cytokines, including IL-21 (Wang et al., 2015). The impaired T H17 cytokine expression in Icosl −/− mice correlated with attenuated liver granulomatous inflammation around parasite eggs and the significant reduction in hepatic fibrosis in those mice as compared with wild-type controls (Wang et al., 2015).
Interestingly, IL-21 does not directly promote the production of the Schistosoma egg-induced IL-17 production by antigenspecific CD4 + T cells. Antibody neutralization of IL-21 in a DC-CD4 + T cells co-culture setting, in which DCs are pulsed with egg antigens and co-cultured with naïve CD4 + T cells, did not impair the antigen-specific IL-17 production by antigen-specific CD4 + T cells (Shainheit et al., 2008). This is consistent with studies demonstrating that the lack of