INTERFER(ON)ing Persistence: During persistent viral infections, a dysregulated immune response fails to control the infection. Wilson et al. (p. 202 ) and Teijaro et al. (p. 207 ; see the Perspective by Odorizzi and Wherry ) show this occurs because type I interferons (IFN I), critical for early responses to viral infection, contribute to the altered immunity seen during persistent infection. Antibody blockade of IFN I signaling during chronic lymphocytic choriomeningitis virus (LCMV) in mice resulted in reduced viral titers at later stages of infection, reduced expression of inhibitory immune molecules and prevented the disruptions to secondary lymphoid organs typically observed during persistent infection with LCMV. Whether type I IFNs are also detrimental to persistent viral infection humans, such as HIV and hepatitis C virus, remains to be determined.

T cell division is an intense metabolic process, and meeting its demands requires extensive metabolic reprogramming of the cell. Bensinger and colleagues demonstrate that SREBPs are critical for this reprogramming. Newly activated CD8+ T cells reprogram their metabolism to meet the extraordinary biosynthetic demands of clonal expansion; however, the signals that mediate metabolic reprogramming remain poorly defined. Here we demonstrate an essential role for sterol regulatory element–binding proteins (SREBPs) in the acquisition of effector-cell metabolism. Without SREBP signaling, CD8+ T cells were unable to blast, which resulted in attenuated clonal expansion during viral infection. Mechanistic studies indicated that SREBPs were essential for meeting the heightened lipid requirements of membrane synthesis during blastogenesis. SREBPs were dispensable for homeostatic proliferation, which indicated a context-specific requirement for SREBPs in effector responses. Our studies provide insights into the molecular signals that underlie the metabolic reprogramming of CD8+ T cells during the transition from quiescence to activation.

Controlling Chronic Viral Infections: Chronic viral infections such as HIV and hepatitis B and C viruses are major public health concerns. T cell—mediated immune responses are critical for controlling viral infections. In contrast to acute infections, chronic viral infections are characterized by “exhausted” cytotoxic CD8 ⁺ T cells, cells which exhibit reduced proliferative capacity, cytokine secretion, and cytotoxicity. Treatments that reverse exhaustion result in increased viral control. Despite their exhaustion, these CD8 ⁺ T cells eventually help to control chronic infections by killing virally infected cells, and require CD4 ⁺ T cell help to do so. How do CD4 ⁺ T cells provide help to CD8 ⁺ T cells during chronic infection (see the Perspective by Johnson and Jameson )? Elsaesser et al. (p. 1569 , published online 7 May), Yi et al. (p. 1572 , published online 14 May), and Fröhlich et al. (p. 1576 , published online 28 May) now show that the cytokine, interleukin-21 (IL-21), known to be critical for the differentiation of certain CD4 ⁺ T cell effector subsets, is an essential factor produced by CD4 ⁺ T cells that helps CD8 ⁺ T cells to control chronic lymphocytic choriomeningitis virus infection in mice. Acute and chronic infections resulted in differing amounts of IL-21 production by virus-specific CD4 ⁺ T cells. CD8 ⁺ T cells required IL-21 directly, and when CD8 ⁺ T cells were unable to signal through IL-21 or IL-21 was not available, they were reduced in number, exhibited a more exhausted phenotype, and were not able to control the virus. In contrast, the absence of IL-21–dependent signaling did not affect primary CD8 ⁺ T cell responses to acute infection or responses to a viral rechallenge, suggesting that differentiation of memory CD8 ⁺ T cells is independent of IL-21.