Interleukin-21 administration leads to enhanced antigen-specific T cell responses and natural killer cells in HIV-1 vaccinated mice

Highlights

• ​Mouse IL-21 could not increase antibody binding capacity to HIV-1 GP140.

• Mouse IL-21 enhanced Th1 type immune response.

• Mouse IL-21 increased the percentages of HIV-1 specific CD4+ T and CD4+ TEM cells.

• ​Mouse IL-21 increased HIV-1 specific multifunctional CD4+ T and CD4+ TEM cells.

• Mouse IL-21 increased the frequency of NK cells.

Abstract

Interleukin-21 (IL-21), which belongs to IL-2 γ chain receptor cytokine family, is as an important regulator of immune responses. In this study, we developed a novel strategy for immunizing mice with a DNA/vaccinia/protein vaccine in the presence or absence of mouse IL-21 (mIL-21) to evaluate whether mIL-21 could enhance immune responses. Our results demonstrated that co-immunization with mIL-21 did not increase significantly the capacity of vaccine induced antibodies to bind to HIV-1 GP140. An effect of mIL-21 in adjusting the efficacy of HIV-1 vaccine through enhancing Th1 type immune response was however observed. The frequencies of HIV-1-specific cytokine-producing CD4+ T and CD4+ TEM cells, especially multifunctional T cell responses, were significantly increased by co-administrating with mIL-21. A significant increase was also observed in the frequency of NK cells in mIL-21 adjuvant groups. Taken together, combination of mIL-21 with HIV-1 vaccines led to distinct enhancement of NK cells and T cell immune responses associated with immune protection.

Introduction

Acquired immunodeficiency syndrome (AIDS) is mainly caused by Human immunodeficiency virus-1 (HIV-1) infection and threatens human health and life. Vaccination has long been a very important measure to prevent infection of pathogens [1]. HIV-1 vaccines have been developed for several decades, however, a safe and effective HIV-1 vaccine remains elusive [2]. Various HIV-1 vaccines, including DNA vaccines [3], replication-competent virus vector vaccine [4], [5] and protein vaccines [6] have been various designed to boost immune responses, control virus replication and reduce the rate of HIV-1 infection.

As an important strategy to improve immune response, cytokine adjuvant, including IFN-γ, IL-2, IL-12 and IL-15, could enhance immune response and has been widely used in vaccine research in recent years [7], [8], [9], [10]. Interleukin-21 (IL-21) is produced mainly by CD4+ T cells and is a member of IL-2 γ chain receptor cytokine family, including IL-2, IL-4, IL-7, IL-9 and IL-15 [11], [12]. The cytokine family utilizes a common γ chain in their individual receptor complexes to deliver intracellular signals in target cells. IL-21 receptor is broadly expressed on T, B, NK, NKT cells, dendritic cells, keratinocytes, and macrophages [13], [14]. Thus, IL-21 has a diverse role in regulating immune responses. IL-21 is involved in the regulation of innate and adaptive immunity, which makes it an ideal candidate for vaccine development vaccines [15]. Recent clinical trials demonstrated that IL-21 had antitumor activity in patients with metastatic melanoma and relapsed/refractory indolent non-Hodgkin’s lymphoma [16]. Cui et al. demonstrated that IL-21 had a positive effect on controlling chronic viral infection and increasing the survival rate of HSV-1-infected mice [17]. Ex vivo studies demonstrated that, as an immunotherapeutic agent, IL-21 could regulate immune responses in chronic hepatitis B and C viral infections [18], [19]. Other studies have investigated the immunotherapeutic property of IL-21 in acute and chronic simian immunodeficiency virus (SIV) infection [20], [21]. IL-21 protein shows promise for its effects on humoral and cellular immunity and may be available as an adjuvant [22].

We hypothesized that a mIL-21 DNA and protein adjuvant could be co-administered to enhance specific immune responses against HIV-1 using a DNA prime and vaccinia/protein boost strategy. This proved to be a successful strategy for boosting innate and cellular immune responses that holds promise for future HIV vaccine development.