br STAR Methods br Acknowledgments This work was supported b

STAR★Methods
Acknowledgments This work was supported by the American Diabetes Association (grant 1-12-BS-161 to J.D.P.), an NIH predoctoral T32 in Autoimmunity and Immunopathology grant (AI089443-05 to D.M.P.), the NIH (grant DK099550 to H.M.T.), the American Association for Cancer Research (Stand Up To Cancer, grant SU2C-AACR-IRG-04-16 to G.M.D.), and an NIH Director’s New Innovator Award (DP2AI136598 to G.M.D.). The authors would also like to thank Drs. Matthew F. Brown and Brian J. Leibowitz for their critical reading of the manuscript.
Introduction Type I interferons (IFNs) are innate molecules secreted by different cells upon infection [1]. They comprise several isoforms of IFN-α, one isoform of IFN-β, and the less characterized IFN-ε, IFN-κ, IFN-ω, IFN-δ, and IFN-τ. All type I IFNs act both in autocrine and paracrine fashions by binding to heterodimeric receptors composed of IFNAR1 and IFNAR2 subunits [2]. The name “interferon” was coined in concomitance with their discovery, and it was inspired by what is historically considered to be the main role for these molecules, i.e. interfering with pathogen replication [3,4]. Indeed, release of type I IFNs is one of the most potent mechanisms of innate immunity against viruses and other intracellular pathogens. However, growing evidence is pointing to a multifaceted role for type I IFNs, with either beneficial or detrimental effects in the fight against infection. This pleiotropic role is mainly due to the different cellular sources, timing and target cells for type I IFNs [5]. For instance, we and others have recently described how type I IFNs released upon lymphocytic choriomeningitis virus (LCMV) infection can have a negative impact on antiviral humoral responses by inducing apoptosis of virus-specific Misoprostol activated early on [[6], [7], [8], [9]]. The conflicting roles of type I IFNs in infection and cancer have been extensively reviewed elsewhere [5,[10], [11], [12]]. Here, we will discuss recent studies that investigated the role of type I IFNs in CD4+ T cell activation and polarization.
CD4+ T cells are key players of adaptive immunity. Naïve CD4+ T cells are primed in secondary lymphoid organs (SLOs) upon binding of MHCII-peptide complexes and costimulatory molecules. Both these signals are provided by professional antigen-presenting cells (APC), mostly dendritic cells (DC), which have encountered and processed antigens either in the periphery or in SLOs [[13], [14], [15]]. Following the priming phase, antigen-specific naïve CD4+ T cells undergo clonal expansion and effector differentiation. During these processes, CD4+ T cells are exposed to a milieu enriched in cytokines produced by many cells including infected cells, DCs, and stromal cells. CD4+ T cells sense these cytokines and activate differentiation programs that result in their polarization towards specialized T helper cell subsets [16,17]. Infection by viruses or intracellular bacteria mainly leads to the generation of Th1 and T follicular helper (Tfh) cells. Th1 cells express the master transcription factor T-bet and produce high levels of IFN-γ, which promotes macrophage activation and enhances CD8+ T cell responses [18,19]. By contrast, Tfh cells migrate to B cell follicles where they specifically interact with cognate antigen-specific B cells and participate in germinal center (GC) reactions to ensure the generation of high-affinity, class-switched antibodies [20,21]. Both CD8-mediated cellular and B cell-mediated humoral responses are essential for proper infection control, and usually co-exist in a fine-tuned equilibrium in order to optimize anti-pathogen immunity [[22], [23], [24]]. The molecular and cellular determinants of CD4+ T cell differentiation into Th1 or Tfh cells in vivo, and hence the relative balance between cellular and humoral immunity, are incompletely understood [[25], [26], [27]]. Research in the field is complicated by the plasticity of T helper cell subsets [27] and the pleiotropic nature of many cytokines. Nonetheless, type IFNs are emerging as critical factors regulating antiviral CD4+ T cell fate.