Controlling Chronic Viral Infections

Science Signaling  23 Jun 2009:
Vol. 2, Issue 76, pp. ec210
DOI: 10.1126/scisignal.276ec210

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 that 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., Yi et al., and Fröhlich et al. 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.

A. Fröhlich, J. Kisielow, I. Schmitz, S. Freigang, A. T. Shamshiev, J. Weber, B. J. Marsland, A. Oxenius, M. Kopf, IL-21R on T cells is critical for sustained functionality and control of chronic viral infection. Science 324, 1576–1580 (2009). [Abstract] [Full Text]

H. Elsaesser, K. Sauer, D. G. Brooks, IL-21 is required to control chronic viral infection. Science 324, 1569–1572 (2009). [Abstract] [Full Text]

J. S. Yi, M. Du, A. J. Zajac, A vital role for interleukin-21 in the control of a chronic viral infection. Science 324, 1572–1576 (2009). [Abstract] [Full Text]

L. D. S. Johnson, S. C. Jameson, A chronic need for IL-21. Science 324, 1525–1526 (2009). [Summary] [Full Text]