In 1998, Allan Zajac published a watershed paper highlighting the role of CD4 T cell help in maintaining functional CD8 T cell responses in a mouse model of chronic viral infection. Zajac’s study, conducted when he was a researcher in Rafi Ahmed’s lab at Emory, lit the fuse for an explosion of new data on T cell exhaustion and dysfunction, including the research identifying molecules such as PD-1 and Tim-3 that may be amenable to therapeutic targeting.
Zajac now runs his own lab at the University of Alabama, and this week John Yi from his group has published new data highlighting the role of IL-21 in controlling a chronic viral infection, using the same model of LCMV infection in mice. In one of those occasional examples of scientific kismet, Heidi Elsaesser and colleagues from UCLA simultaneously publish parallel findings. The papers are posted to Science Express. Both groups of researchers report that production of the cytokine IL-21 by LCMV-specific CD4 T cells is vital to the maintenance of functional LCMV-specific CD8 T cells. Mice bred to genetically lack IL-21 (IL-21 knockout mice) show a failure to control chronic LCMV infection that is similar to that seen in CD4-deficient mice.
Yi’s paper also shows that administration of exogenous IL-21 can restore CD8 T cell function in CD4-deficient mice, although this was a double-edged sword in the LCMV model because exuberant CD8 T cell activity is associated with immunopathology, and most of the mice had to be euthanized. The concluding comments are therefore understandably careful: "we anticipate that the cautious development of approaches to modulate the levels of IL-21, or regulate the induction of cellular subsets that generate IL-21, will provide new therapeutic opportunities to improve immunity to diseases that require CD8+ T cell responses to be controlled, such as chronic viral infection and tumors."
There are already data published from phase I trials of recombinant IL-21 in cancer, suggesting that the treatment was tolerable and may have some limited activity. In HIV, a 2007 paper reported that addition of IL-21 to CD8 T cells in vitro was associated with increased perforin expression. More recently, a study found that circulating IL-21 levels are decreased in people with HIV and correlate with CD4 T cell counts.
6/1/09 Update: Another paper has just been published in Science Express, reporting complementary data from studies in mice genetically lacking the IL-21 receptor (IL-21R), abstract and link added below.
Science DOI: 10.1126/science.1175194
Published Online May 14, 2009
John S. Yi 1, Ming Du 1, Allan J. Zajac 1*
1 Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294–2170, USA.
Understanding the factors that regulate the induction, quality, and longevity of antiviral T cell responses is essential for devising rational strategies to prevent or combat infections. In this study, we show that interleukin-21 (IL-21), likely produced by CD4+ T cells, directly influences the generation of polyfunctional CD8+ T cells and that the number of CD4+ T cells that produce IL-21 differs markedly between acute and chronic infections. Strikingly, IL-21 regulates the development of CD8+ T cell exhaustion and the ability to contain chronic lymphocytic choriomeningitis virus infection. Thus, IL-21 serves as a critical helper factor that shapes the functional quality of antiviral CD8+ T cells and is required for viral control.
Science DOI: 10.1126/science.1174182
Published Online May 7, 2009
Heidi Elsaesser 1, Karsten Sauer 2, David G. Brooks 1*
1 Department of Microbiology, Immunology and Molecular Genetics and the UCLA AIDS Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
2 Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
CD4+ and CD8+ T cell functions are rapidly aborted during chronic infection, preventing viral clearance. CD4+ T cell help is required throughout chronic infection to sustain CD8 T cell responses; however, the necessary factor(s) provided by CD4+ T cells are currently unknown. Using a mouse model of chronic viral infection, we demonstrate that interleukin-21 (IL-21) is an essential component of CD4+ T cell help. In the absence of IL-21 signaling, despite elevated CD4+ T cell responses, CD8+ T cell responses are severely impaired. CD8+ T cells directly require IL-21 to avoid deletion, maintain immunity, and resolve persistent infection. Thus, IL-21 specifically sustains CD8+ T cell effector activity and provides a mechanism of CD4+ T cell help during chronic virus infection.
Science DOI: 10.1126/science.1172815
Published Online May 28, 2009
Anja Fröhlich 1, Jan Kisielow 1, Iwana Schmitz 1, Stefan Freigang 1, Abdijapar T. Shamshiev 1, Jacqueline Weber 1, Benjamin J. Marsland 1, Annette Oxenius 2, Manfred Kopf 1
1 Molecular Biomedicine, Institute of Integrative Biology, ETH Zurich, Switzerland. 2 Institute of Microbiology, ETH Zurich, Switzerland.
Chronic viral infection is often associated with dysfunction of virus specific T cells. Our studies using Il21r-deficient (Il21r–/–) mice now suggest that interleukin (IL)-21 is critical for long-term maintenance and functionality of CD8+ T cells and control of chronic lymphocytic choriomeningitis virus infection in mice. Cell-autonomous IL-21 receptor (IL-21R)–dependent signaling by CD8+ T cells was required for sustained proliferation and cytokine production during chronic infection. Notably, Il21r–/– mice showed normal CD8+ T cell expansion, effector function, memory homeostasis, and recall responses during acute and after resolved infection with several other nonpersistent viruses. These data suggest that IL-21R signaling is required for the maintenance of polyfunctional T cells during chronic viral infections and have implications for understanding the immune response to other persisting antigens, such as tumors.