Type‐I IFN drives the differentiation of short‐lived effector CD8⁺ T cells in vivo

Abstract

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 ...

Nanoparticle Adjuvant Sensing by TLR7 Enhances CD8+ T Cell–Mediated Protection from Listeria Monocytogenes Infection

“…Interestingly, absence of IFNAR did not abrogate totally the effect of PapMV on the number of OVA-specific CD8 + T cells. In past years, several studies have shown that direct stimulation of T cells by IFN-I was required for optimal CD8 + T cell responses (45,46). In our case, it seems that IFN-I produced following PapMV immunization acts not only on CD8 + T cell but also directly on injected BMDC because IFN-I produced in Ifnar KO mice can act only on these cells because they are the only ones expressing the IFNAR.…”

Therapeutic Activity of High-Dose Intratumoral IFN-β Requires Direct Effect on the Tumor Vasculature

“…Low levels of transiently produced type I IFNs are associated with productive T cell priming, including activation of T cells in the tumor context (3,4). However, high and/or persistent levels of type I IFNs have been associated with strong effector T cell induction but poor generation of immunological memory (37,38). In the chronic lymphocytic choriomeningitis virus model, blockade of the type I IFN receptor has been reported to restore functional immunity in vivo (37).…”

NK cells and interferons

“…These studies support previous observation showing that type I IFNs are important to drive CD8 + T cell differentiation. Indeed, T cells that do not perceive type I IFN signals fail to accumulate during certain infections while the level of MHC I expression by T cells in HCV patients correlates with virus control [103][104][105][106][107].…”