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

Abstract

Chronic viral infection is often associated with the dysfunction of virus-specific T cells. Our studies using Il21r-deficient (Il21r-/-) mice now suggest that interleukin-21 (IL-21) is critical for the long-term maintenance and functionality of CD8+ T cells and the 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 cell proliferation and cytokine production during chronic infection. 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.

Dendritic cell‐based therapeutic vaccine elicits polyfunctional HIV‐specific T‐cell immunity associated with control of viral load

“…Moreover, the data also indicate that IL-13-and IL-21-secreting HIV-specific T cells before ATI are associated with a lower viral replication following ATI, an immunological feature described in elite controllers [14,15]. As observed following therapeutic immunization of patients or in models of SIV pathogenesis, the ability to produce IL-2 CD4 + T cells appears to be critical for the maintenance of the proliferative capacity of CD8 + T cells [16][17][18][19].…”

Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection

“…Alternatively, Schmitt et al (43) showed that IL-12 from PRR-stimulated DCs directly acts on memory CD4 + T cells to promote the secretion of IL-21. It is plausible that differences in the abundance of IL-21-dependent signals produced by CD4 + T cells are involved in the increased exhaustion of polyfunctional CD8 + T cells (37,38) in CP-Ds relative to CP-Ns; this awaits formal examination.…”

“…1, Supplemental Table 1). Although the requirement for CD4 + T cell help throughout chronic infection to sustain CD8 + T cell function (37,38) is not in dispute, PRRactivated DCs could represent a backup mechanism for situations in which CD4 responses are defective. This would be in keeping with findings by other investigators in which the adoptive transfer of autologous DCs loaded in vitro with whole-inactivated HIV-1 or therapeutic vaccination with a recombinant viral vector, both of which recruit functional DCs into the APC pool, induces protective antiviral immunity and viral suppression in the setting of chronic HIV-1 infection (39) and synergizes with PD-L1 neutralization to clear infection in CD4 + T cell help-deficient LCMV clone 13-infected mice (40), respectively.…”

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.…”