A Vital Role for Interleukin-21 in the Control of a Chronic Viral Infection

Abstract

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.

Antigen-specific CD4 T-cell help rescues exhausted CD8 T cells during chronic viral infection

“…One possibility is that soluble factors produced by activated CD4 T cells act directly on exhausted CD8 T cells. Recent studies have shown that IL-21 produced by CD4 T cells plays a critical role in maintaining CD8 T-cell function during chronic LCMV infection (36)(37)(38). IL-21 has also been shown to enhance HIV-specific CD8 T cell function in vitro (39).…”

L’interleukine-21, une cytokine clé dans le contrôle du VIH et d’autres infections virales chroniques

“…Cependant, les éléments régulateurs clés produits par les cellules T CD4 + et nécessaires à l'obtention d'une réponse antivirale complète et efficace étaient jusqu'à récemment, mal compris, voire inconnus. Trois études récentes réalisées sur des mo dèles in vivo murins d'infection virale persistante par le lymphocytic choriomeningitis virus (LCMV) ont démontré le rôle clé de l'IL-21 dans la réponse antivirale [14][15][16]. Lors de ces études, les auteurs ont utilisé deux souches différentes de LCMV (clone 13 et Armstrong) qui possèdent une pathogénicité différente chez l'animal inoculé.…”

“…L'injection directe d'IL-21 à des souris ne possédant pas de cellules T CD4 + a permis de restaurer les fonctions antivirales exprimées par les cellules T CD8 + ainsi que de réduire la charge virale chez ces souris [16]. L'IL-21 ne semble donc pas être nécessaire à la génération des cellules T CD8 + spécifiques du virus, mais elle serait importante pour la qualité de la réponse antivirale [16]. Ces études suggèrent le rôle indispensable de l'IL-21 au stade chronique de l'infection, plutôt qu'au stade de l'infection aiguë.…”

Role of interleukin-21 in HBV infection: friend or foe?

“…IL-21 secreted by activated CD4 1 T cells was essential for the maintenance of specific CD8 1 T-cell functions and control of viremia in lymphocytic choriomeningitis virus infection. [6][7][8] CD4 1 T cells from individuals with sustained immune control of HIV-1 infection produced larger amounts of IL-21 upon stimulation with phorbol myristate acetate/ionomycin or HIV-1 gag peptides. Of note, exogenous IL-21 significantly increased HIV-1-specific CD8 1 T-cell effector functions.…”

“…In mouse models of chronic lymphocytic choriomeningitis virus infection, IL-21 produced by virus-specific CD4 1 T cells was essential for sustaining antiviral functions of CD8 1 T cells and preventing them from immune exhaustion. [6][7][8] Acutely-resolved hepatitis C virus was characterized by strong Th1/Th17 responses with specific expansion of IL-21-producing CD4 1 T cells and increased IL-21 levels in the plasma. 9 In patients with HIV-1 infection, reduced IL-21 production could be a contributing factor to the compromised cellular and humoral immune responses.…”