Direct type I interferon (IFN) signaling on T cells is necessary for the proper expansion, differentiation, and survival of responding T cells following infection with viruses prominently inducing type I IFN. The reasons for the abortive response of T cells lacking the type I IFN receptor (Ifnar1(-/-)) remain unclear. We report here that Ifnar1(-/-) T cells were highly susceptible to natural killer (NK) cell-mediated killing in a perforin-dependent manner. Depletion of NK cells prior to lymphocytic choriomeningitis virus (LCMV) infection completely restored the early expansion of Ifnar1(-/-) T cells. Ifnar1(-/-) T cells had elevated expression of natural cytotoxicity triggering receptor 1 (NCR1) ligands upon infection, rendering them targets for NCR1 mediated NK cell attack. Thus, direct sensing of type I IFNs by T cells protects them from NK cell killing by regulating the expression of NCR1 ligands, thereby revealing a mechanism by which T cells can evade the potent cytotoxic activity of NK cells.

One Sentence SummaryWe demonstrate that continued presence of CXCR5 +/+ TFH cells throughout chronic viral infection is dispensable for maintenance of overall virus-specific antibody titers but is vital for the generation of virus-neutralizing antibodies and eventual control of the infection.

Two subsets of CD81 T cells are generated early during an immune response; one of these subsets forms the memory pool, known as memory precursor effector cells (MPECs), identified by high expression of CD127 and low expression of KLRG1, whereas the other subset forms short-lived effector cells (SLECs) identified by low expression of CD127 and high expression of KLRG1. Here, we studied in vivo the role of type-I IFN in this fate decision. We found that under priming conditions dominated by type-I IFN, as observed in lymphocytic choriomeningitis virus (LCMV) infection, type-I IFN signaling directly impacted the regulation of T-bet and thus the early fate decision of CD8 1 T cells. In the absence of type-I IFN signaling, CD8 1 T cells failed to form SLECs but could form MPECs that give rise to functional memory CD8 1 T cells. Together, these findings identify type-I IFN as an important factor driving SLEC differentiation and thus instructing the early division between the effector and memory precursor CD8 1 T-cell pool.Key words: CD8 1 T cells . Differentiation . Type I interferon . Viral infection Supporting Information available online IntroductionIn response to an acute infection CD8 1 T cells rapidly expand to form a pool of effector cells with cytolytic and cytokine secretion activity. The pool of early effector cells can be divided into two main subsets according to their ability to form terminally differentiated effector cells or long-lived memory cells; referred to as short-lived effector cells (SLECs), CD127 low and KLRG1 high , and as memory precursor effector cells (MPECs), CD127 high and KLRG1 low , respectively [1,2]. There is strong evidence that inflammatory cytokines present during CD8 1 T-cell priming play a key role in the effector and memory fate decision process [3][4][5]. In support of this notion it has been shown that IL-12 signaling is mandatory for driving activated CD8 1 T cells toward an SLEC phenotype upon infection with Listeria monocytogenes but not vesicular stomatitis virus (VSV), vaccinia virus (VV) or lymphocytic choriomeningitis virus (LCMV) [5]. Similar to IL-12, type-I IFN signaling has been shown to support the proliferation and development of cytolytic activity of CD8 1 T cells in vitro [6][7][8][9][10] and can act as an adjuvant in vivo to a variety of stimuli [3,[11][12][13][14]. (Fig. 3B). As the differences in the expression of CD25 and CD62L were already apparent during the initial cell divisions, we reasoned that very early following infection activated CD8 1 T cells undergo a lineage choice and that type-I IFN plays a crucial role in this decision.Having analyzed the very early stages of this differentiation process we next looked at the long-term development of memory cells by phenotypically analyzing cell surface marker expression profiles on WT and IFNAR À/À P14 cells in the blood of LCMV8.7and VVG2 co-infected mice (Fig. 3C). This longitudinal analysis revealed that IFNAR À/À P14 cells initially begin to down-regulate surface CD62L expression but after day 3 the ...

Keywords: CD4 + T cell r CD40-signaling r Secondary CD8 + T-cell responses r T-cell help r Vaccinia virusAdditional supporting information may be found in the online version of this article at the publisher's web-site

Persistent virus infections with non‐ or poorly cytopathic viruses are commonly associated with B cell dysregulations. These include the induction of hypergammaglobulinemia and the emergence of virus‐unspecific antibodies. These seemingly unspecific antibody responses interfere with the virus‐specific humoral immunity and contribute to delayed virus control. Whether these virus‐unspecific antibodies are induced in the B cell follicle or at extrafollicular sites and whether one specific CD4 T cell subset is involved in the polyclonal B cell activation is unclear. Here we studied virus‐unrelated IgG antibody responses against self or foreign antigens in the context of persistent lymphocytic choriomeningitis virus (LCMV) infection. We found that the LCMV‐unspecific antibody response is short‐lived and induced predominantly at extrafollicular sites and depends on the presence of LCMV‐specific CD4 T cells. Our data support a scenario in which activated, virus‐specific CD4 T cells provide help to non‐specific B cells at extrafollicular sites, supporting the production of virus unspecific IgG antibodies during persistent viral infection.