IL-21R on T Cells Is Critical for Sustained Functionality and Control of Chronic Viral Infection

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.