Elucidating the role of T cells in protection against and pathogenesis of dengue virus infections

Abstract

Dengue viruses (DENV) cause significantly more human disease than any other arbovirus, with hundreds of thousands of cases leading to severe disease in thousands annually. Antibodies and T cells induced by primary infection with DENV have the potential for both positive (protective) and negative (pathological) effects during subsequent DENV infections. In this review, we summarize studies that have examined T-cell responses in humans following natural infection and vaccination. We discuss studies that support a role for T cells in protection against and those that support a role for the involvement of T cells in the pathogenesis of severe disease. The mechanisms that lead to severe disease are complex, and T-cell responses are an important component that needs to be further evaluated for the development of safe and efficacious DENV vaccines.

Figure 1. Interactions between multiple components of the immune system during dengue virus infection

The primary targets of DENV replication are monocytes, macrophages and dendritic cells, but B cells may also be infected with DENV. Antibodies secreted by B cells can mediate a wide range of functions including neutralization, ADE, ADCC and CDL. Virus-infected target cells secrete cytokines and chemokines and attract T cells. Viral peptides are presented on MHC class I and class II presentation pathways to CD8⁺ and CD4⁺ T cells, respectively. CD4⁺ T cells predominantly produce cytokines but are capable of lysing virus-infected cells, and CD8⁺ T cells lyse virus-infected cells and produce cytokines. The role of γδ T cells, Th17 and NK cell participation in the antiviral immune defense mechanisms requires further investigation. Question marks in the figure indicate that the evidence is not clear. The result of the cascade of immune activation leads to endothelial cell permeability and plasma leakage. Ab: Antibody; ADCC: Antibody-dependent cell-mediated cytotoxicity; ADE: Antibody-dependent enhancement; Ag: Dengue antigen; BcR: B-cell receptor; C1q: Subcomponent of complement pathway; CDL: Complement-dependent lysis; DENV: Dengue viruses; FcγR: Fc gamma receptor; KIR: Killer-like immunoglobulin receptor; NEUT: Neutralization; NK: Natural killer; TcR: T-cell receptor; Th17: T helper 17.

Figure 2. Disease outcome is multifactorial

Every person can generate ‘optimal’ or ‘suboptimal’ responses to individual DENV-specific T-cell epitopes. The total T-cell response to DENV in an individual is the cumulative response to multiple epitopes. A favorable clinical outcome occurs when overall ‘optimal’ T-cell responses occur in the context of protective host, genetic and other immunological factors. An unfavorable clinical outcome occurs when ‘suboptimal’ T-cell responses occur in the context of pathogenic host, genetic and other immunological factors. DENV: Dengue viruses.