Project

IL-9 ; IL-21; viral infection; T cell responses

Lead
Lay summary
The common gamma-chain (gc) cytokines IL-2, IL-7, IL-15, and IL-21 have been shown to determine the short-term and long-term fate of T cell responses during acute and chronic viral infection in some way or other. IL-7 and IL-15 promote homeostatic proliferation of memory cells, IL-2 is essential for CD8 expansion following secondary infection. We and others have shown that IL-21 prevents CD8 T cell exhaustion during chronic viral infection by sustaining long-term functionality of anti-viral CD8 T cell responses. However, a detailed understanding how IL-21 maintains T cell functionality in chronic viral infection remains unclear, especially in light of the finding that IL-21 is dispensable for acute effector, memory, and recall CD8+ T cell responses to infection with viruses that are typically cleared during acute infection. We have evidence that chronic viral infection is associated with the expansion of regulatory T cells (Tregs) and that this is prevented by IL-21. Thus, we are currently studying the roles of Tregs in chronic LCMV infection and the mechanism of their suppression by IL-21. In addition, we will use IL-21reporter mice to visualize dynamics of IL-21 production and to identify IL-21-producing cells during anti-viral responses and other immune responses depending on IL-21 (i.e. Th2-mediated allergic airway inflammation). The IL-9R also associates with the gc receptor subunit. IL-9 is known to promote defense to gastrointestinal nematodes, anaphylaxis to allergen challenge at mucosal surfaces, and allergic lung inflammation. Few reports also have suggested a role IL-9 in viral infection. Using IL-9 loss-of-function and gain-of-function experiments, we are currently investigating its function in acute and chronic viral infection   Taken together, these studies will further unravel the role of gc cytokines in determining the fate of T cells and control of acute and chronic viral infection.

Direct link to Lay Summary

Last update: 21.02.2013

Active participation

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Over the past 5 years, cytokines that belong to a subfamily of the type 1 four-helix-bundle cytokines, which all utilize the ?c cytokine receptor in combination with a unique cytokine specific receptor chain including IL-2, IL-7, IL-15, and IL-21, have been shown to determine the short-term and long-term fate of T cell responses in acute and chronic viral infection. IL-7 and IL-15 promote homeostatic proliferation of memory cells, IL-2 is essential for CD8 expansion following secondary infection, and IL-21 prevents CD8 T cell exhaustion during chronic viral infection. A detailed mechanism how IL-21 maintains T cell functionality in chronic viral infection remains unclear, especially in light of the finding that IL-21 is dispensable for acute effector, memory, and recall CD8+ T cell responses to infection with viruses that are typically cleared after the acute response. We have found that chronic viral infection is associated with the expansion of Tregs, which is prevented by IL-21. Thus, we hypothesize that IL-21 protects from T cell exhaustion during chronic infection by suppression of Tregs and propose to: 1: Investigate anti-viral T cell responses and viral clearance in wild-type and IL-21R-/- mice using a Foxp3+ Treg loss-of-function and gain-of-function approach. Notably, CD8+ T cells lacking either the IL-2Ra or the IL-21R show normal expansion, contraction and maintenance of long-term memory following resolved infection. We hypothesize that IL-2 and IL-21 have overlapping activities in the generation of memory T cells and the absence of one can be compensated by the presence of the other. Thus, we propose to:2: Study viral infection in IL-2Ra/IL-21R double-deficient mice.IL-21 can be produced by a variety of T cell subpopulations. To understand the role of IL-21 in immune responses it is important to determine dynamics of IL-21 production and identify IL-21-producing cells. However, measurement of IL-21 is difficult due to low frequency of IL-21 producing cells and low-level production per cell in vivo. To overcome this obstacle, we propose to:3: Generate Bac transgenic IL-21-reporter mice The IL-9R also associates with and signals through the ?c chain. IL-9 is known to promote clearance of gastrointestinal nematodes, anaphylaxis to allergen challenge at mucosal surfaces, and allergic lung inflammation. However, studies on the role of IL-9 in viral infection are scarce. We have observed that IL-9R-/- mice show elevated IFN? and TNFa production throughout the course of resolved and chronic infection with LCMV. Thus we hypothesize that IL-9 interferes with pluripotency of T cell responses and efficient viral clearance. To study this we propose to4: Determine the role of IL-9 in acute and chronic viral infection by IL-9 loss-of-function and gain-of-function experimentsTaken together, these studies will further unravel the role of ?c cytokines in determining the fate of T cells and control of acute and chronic viral infection.