T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses

Abstract

Reactions to pathogens are usually tuned to effect immunity and limit tissue damage. Several host counterinflammatory mechanisms inhibit tissue damage but these may also act to constrain the effectiveness of immunity to acute infections, as we demonstrate in mice acutely infected with influenza A virus (IAV). We show that compared with wild type (WT), galectin-9 knockout (G9KO) mice mounted a more robust acute phase virus-specific CD8 T-cell response as well as higher and more rapid virus-specific serum IgM, IgG, and IgA responses and also cleared virus more rapidly than did WT mice. Blocking galectin-9 signals to Tim-3-expressing cells using a Tim-3 fusion protein resulted in improved immune responses in WT mice. When IAV immune mice were challenged with a heterologous IAV, the secondary IAV-specific CD8 T-cell responses were fourto fivefold higher in G9KO compared with WT mice. Our results indicate that manipulating galectin signals may represent a convenient approach to improve immune responses to some vaccines.T he host immune response to pathogens needs precise regulation to minimize tissue damage while still achieving defense (1, 2). Some bystander tissue damage usually happens because several host defenses can destroy cells or orchestrate inflammatory reactions. With chronic infections, for example, immune-mediated tissue damage would be more severe were it not for several cellular and chemical host components that inhibit inflammatory reactions (1). However, the activity of some of these counterinflammatory mechanisms could act to constrain the efficiency of protective immune components (3). For instance, regulatory T cells (Tregs) can inhibit inflammatory reactions associated with chronic virus infections (4), but the same Treg response can also limit the magnitude of protective immunity to a virus or induced by a vaccine (5, 6). Other host components may also function to limit and help resolve inflammatory reactions. These include some cytokines (7), groups of molecules derived from omega-3 polyunsaturated fatty acids (8), as well as some of the carbohydrate binding proteins of the galectin family (9). Galectin-9 (Gal-9), for example, upon binding to Tim-3 on T cells acts to limit the extent of immunopathological lesions in autoimmunity (10) as well as in some chronic infections (11-13). In the present study, we investigated whether the inhibitory effects of Gal-9 on Tim-3-expressing cells could influence the outcome of acute infection with influenza A virus (IAV). We demonstrate that animals lacking the regulatory effects of Gal-9/Tim-3 triggering mounted superior CD8 T-cell and humoral immune responses and they were more refractory to IAV. Moreover, IAV immune G9KO mice challenged with a heterologous IAV strain generated better virus-specific memory CD8 T-cell responses than WT animals. Our results indicate that manipulating galectin signaling may represent a convenient approach to improve responses to some vaccines. Results Virus-Specific CD8 T cells Up-Regulate Tim-3 Expression after IAVInfection. ...

Increased Levels of Plasma Galectin-9 in Patients with Influenza Virus Infection

“…Furthermore, exogenous Gal-9 administration reduced the efficiency of CD8 T cell-mediated immunity to HSV infection. IAV-specific CD8 T cells from IAV-infected mice undergo apoptosis upon exposure to recombinant Gal-9 in vitro (Sehrawat et al 2009(Sehrawat et al , 2010Sharma et al 2011). We first demonstrated elevated levels of plasma Gal-9 with influenza virus infection in humans.…”

microRNA-22 downregulation of galectin-9 influences lymphocyte apoptosis and tumor cell proliferation in liver cancer

“…As one of the specific ligands of T-cell immunoglobulin and mucin domain 3 (Tim-3), a Th1-specific type 1 membrane protein, Gal-9 is an important inhibitory immune molecule (9). Binding of Gal-9 to Tim-3 causes an inhibitory signal that results in the apoptosis of effector cells, negatively regulates Th1-type immunity and induces tumor immune tolerance and immune evasion (10,11). Subsequently, Gal-9 was identified to be ubiquitously expressed in a variety of tumor tissues and cell lines and its expression level was closely related with malignant tumor prognosis (12).…”

Human Cytomegalovirus Upregulates Expression of the Lectin Galectin 9 via Induction of Beta Interferon

“…Gal-9 can play an important role in virus life cycles. It modulates human immunodeficiency virus type 1 (HIV-1) entry (6,7), while Gal-9-knockout mice exhibit more potent antiviral T-cell responses than wild-type mice (8,9), and infection with Epstein-Barr virus (EBV) modulates Gal-9 expression to evade immune clearance, inducing apoptosis of EBV-specific CD4 ϩ T cells (10,11). We investigated the expression of Gal-9 in the context of HCMV infection both in vivo and in vitro, identifying a novel, virally induced mechanism to promote Gal-9 expression.…”