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  • br Since viral infections result in polarization of na

    2022-01-14


    Since viral infections result in polarization of naïve CD4 T cells into both Th1 and Tfh subsets (although to variable degrees depending on the nature of the pathogen), a lot of effort has been devolved to the question of whether type I IFNs play a role in CD4+ T cell polarization. In vitro studies of naïve CD4+ T cell polarization have shown that type I IFNs are certainly needed for the expression of the Tfh master transcription factor Bcl-6, and to a lower extent for the induction of the Th1 transcription factor T-bet [43]. Interestingly, culture of CD4+ T cells with type I IFNs resulted in the expression of Tfh surface markers CXCR5 and PD-1, but not in IL-21 production. IL-21 is a cytokine produced by fully differentiated Tfh, so what can be inferred from these data is that type I IFNs initiate early Tfh differentiation but other cytokines (e.g. IL-6) are needed to complete the Tfh polarization program. Type I IFNs seem to be required for Tfh differentiation upon immunization in vivo as well; however the target cell(s) responsible for this effect seems to vary according to the experimental setting, ranging from CD4+ T cell themselves to DCs and monocytes [[44], [45], [46]]. The differences in these settings might be explained by the complex cytokine milieu found in vivo, where synergies of type I IFNs with other cytokines such as IL-6 [43,45] and IL-1 [46] might have profoundly different effects on CD4+ T cell polarization (Fig. 2). The notion that type I IFNs drive Tfh differentiation in vivo is not universally accepted, with some studies reporting increased Tfh cell number upon IFNAR blockade during acute LCMV infection [47]. This was also shown in a more stringent setting where Tfh were poised to express Th1-related genes due to impaired STAT3-derived signals. STAT3-deficient CD4+ T cells showed higher sensitivity to type I IFNs, and treatment with IFNAR-blocking proton pump inhibitors reverted the phenotype from Th1 to Tfh [47]. Interestingly, in a setting of LM infection, type I IFN signaling in CD4+ T cells was shown to promote Th1 differentiation, by synergizing with IL-12-derived signals [48]. These data potentially suggest that IFNAR signaling might suppress Tfh and favor Th1 differentiation upon certain infections (Fig. 2). It is worth mentioning, however, that type I IFN signaling during LCMV infection leads to LCMV-specific B cell apoptosis [[6], [7], [8], [9]]. Thus, the detrimental effect of type I IFN on Tfh development upon LCMV infection might be due to an ineffective B cell response, which is required to reach full Tfh differentiation (Fig. 2). Moreover, it was shown that type I IFN signaling results in modest but significant suppression of Tfh cells generated upon infection with a LCMV chronic strain [49]. Whereas blocking type I IFN signaling at the onset of acute or chronic LCMV infection led to increased Tfh cells [47,49], a strikingly opposite result was obtained with CD4+ T cells primed during an established persistent infection [49]. Indeed, transfer of LCMV-specific CD4+ T cells into mice previously infected with a chronic LCMV strain led to suppressed Th1 and heightened Tfh differentiation, and this phenotype was readily reverted when IFNAR was blocked [49]. This effect was not due to signaling of type I IFNs in CD4+ T cells but to the effect of type I IFNs on other yet to be identified cells. The role of type I IFNs on CD4+ T cell responses has been investigated also in the context of malaria infection, with data suggesting that type I IFN signaling in DCs dampens CD4+ T cell activation and differentiation to both Th1 and Tfh cell subsets [[50], [51], [52], [53]].
    Concluding remarks and discussion The studies discussed in this review show that type I IFN signaling can have disparate effects on CD4+ T cell activation, depending on the cells sensing these cytokines, the nature of the pathogen and the stage of the infection. One interpretation might be that the role of type I IFNs changes based on whether the infection is acute or chronic [10], with interferons supporting CD4+ T cell expansion in the acute phase, but inducing their exhaustion during the chronic phase [29,32,42]. Interestingly, one study showed that type I IFNs played distinct roles in polarization of CD4+ T cells depending on whether these cells were primed at the onset or during an ongoing chronic LCMV infection [49]. Indeed, type I IFN signaling promoted Th1 differentiation early on, but inhibited de novo Th1 and favored instead Tfh differentiation during an ongoing infection [49]. This suggests that even within the context of the same infection, IFNAR signaling might lead to opposed effects on CD4+ T cell polarization, depending on the timing of action. Moreover, the role of type I IFNs on CD4+ T cell polarization seem to vary even during acute infections or immunizations [[44], [45], [46]]. Therefore, more than distinguishing between acute and chronic infections, one should perhaps focus on the kinetics, magnitude and targets of type I IFNs in the different immunization/infection settings. For instance, during acute malaria infection IFNAR engagement suppresses CD4+ T cell responses, whereas during acute LCMV infection it supports them [29,54]. One attractive hypothesis might be that the action of type I IFNs is tightly regulated in time and space, and the cytokine milieu generated upon different infections (or at different times during the same infection) adds up to this tight regulation to confer specificity to the IFN-mediated signaling. The molecular and cellular mechanisms regulating the spatiotemporal functions of type I IFNs on CD4+ T cell differentiation remain to be fully elucidated, and might be influenced by, among others, pathogen replication kinetics, tropism, cytokine milieu or cellular target(s) [5,45,47,51]. Combination of conditional knock-out models with timed delivery of blocking antibodies might shed additional light on the complex relationship between type I IFNs and CD4+ T helper cell priming and differentiation.