In this Top Read, Hussain et al. (p. 297) used a helminth infection model in mice to understand mechanisms by which aging impairs the function of virtual memory T (TVM) cells. Helminth infection of young, but not aged mice, resulted in a significant and persistent increase in TVM cell numbers, rather than in naive T (TN) or conventional memory T cells. Relative to these other T cell subsets, isolated TVM cells from young, but not aged mice, featured the highest expression levels of CD124, CD122, and the Eomes transcription factor, consistent with increased IL-4 and IL-15 signaling. Whereas previous experiments demonstrated that IL-4 signaling is not strictly required for TVM expansion, transient blockage of IL-15 signaling demonstrated that IL-15 signaling via trans presentation by splenic conventional dendritic cells drives expansion of TVM cells. Using adoptive transfer experiments with TVM or TN cells in young mice, the authors showed that expansion of TVM cells is a result of their increased proliferation, not a result of TN cell differentiation. In vivo, aged TVM cells, even with complex of IL-15/IL-15Rα administration, proliferated more modestly than did younger TVM cells. Altogether, the data reveal an intrinsic deficit in cytokine signaling associated with age-induced dysfunction of TVM cells and suggest one mechanism by which parasitic immunity declines with age in mammals.

In this Top Read, Resiliac et al. (p. 348) investigated the mechanisms underlying protection from lethal viral infection following low-dose LPS administration. Mice that were pretreated with various doses of LPS were more likely to survive a subsequent inoculation with a typically lethal dose of Sendai virus (SeV), compared with control treatment mice. LPS-primed mice sustained higher numbers of macrophages in the lungs upon viral infection, and several macrophage-associated chemokines, cytokines, and type I IFNs were also increased; neutrophil numbers, however, decreased. Mice deficient for Ifnar, Tlr4, or MyD88 did not demonstrate the same survival advantage afforded by LPS pretreatment of control mice, implicating type I IFN signaling via the TLR4-MyD88 axis in protection from SeV. Therefore, low-dose priming with LPS confers a survival advantage against disease caused by SeV, a paramyxovirus, and this advantage is rooted in the innate immune response via macrophage function and type I IFN signaling.