IL-2/Anti-IL-2 Antibody Complex Enhances Vaccine-Mediated Antigen-Specific CD8+ T Cell Responses and Increases the Ratio of Effector/Memory CD8+ T Cells to Regulatory T Cells

Abstract

IL-2 is well described as a cytokine with two markedly distinct functionalities: as a necessary signal during CD4+ and CD8+ T cell activation/expansion and as an essential cytokine for the maintenance of CD4+CD25+FoxP3+ T cells (regulatory T (TREG) cells) during homeostasis. In this study we demonstrate for the first time that, compared with the use of IL-2 alone, a complex of IL-2 and anti-IL-2 Ab (IL-2 complex) enhances the effectiveness of a viral vaccine in a mouse model with known Ag specificity. IL-2 complex led to an increase in the number of Ag-specific effector/memory CD8+ T cells, cytokine production, and CTL lysis following Ag-specific restimulation in a vaccination setting. Our results further demonstrate that this effect is temporary and declines over the course of a few days after the IL-2 complex treatment cycle. Moreover, in contrast to the use of IL-2 alone, IL-2 complex greatly increased the ratio of effector/memory CD8+ T cells to TREG cells. This phenomenon can thus potentially be used in the enhancement of immune responses to vaccination.

Fine epitope specificity of antibodies against interleukin-2 explains their paradoxical immunomodulatory effects

“…31 In total, the evidence indicates that masking a particular IL-2 antigenic region by immunoenhancing antibodies (the α chain interface) would result in functional masking of a crucial property of IL-2: its ability to promote tolerance, 1 allowing its other facet (enhancement of immune responses) to be fully evident. In such a way, the balance between regulatory and effector cells would be altered, resulting in exacerbated effector responses, as has been described for the immunostimulatory antibody S4B6 in the context of anti-viral vaccination, 7 and anti-tumor responses. 6,8,9 On the other hand, the simultaneous blockade of the interactions with α and β/γ chains by JES6-1A12 mAb provides a rationale for its strong immunoregulatory activity observed in diverse scenarios like autoimmune diseases therapy and transplantation, 10,11,13 and tolerance induction against therapeutic proteins.…”

“…3 The net effect of IL-2-based therapies is the result of the balance between its interactions with different cell populations within the immune system and the whole organism. 4 Since the description of a clear functional dichotomy of immune complexes formed between IL-2 and different monoclonal antibodies (mAbs), 5 the use of such complexes has expanded to multiple experimental settings for either enhancing the effector responses [6][7][8][9] or down modulating immunity. [10][11][12][13] Besides the therapeutic potential of these approaches, 14 immune complexes highlight different features of IL-2 biology.…”

The Role of Interleukin-2 in Memory CD8 Cell Differentiation

“…Thus, when IL-2/anti-IL-2 mAb complexes were injected plus specific antigen to stimulate influenza-specific TCR transgenic CD8 + T-cells in vivo, the complexes increased numbers of proliferating antigen-specific CD8 + cells by 7-fold and conferred the cells with strong effector functions such as IFN-γ production and CTL activity. 66 …”

IL-2/anti-IL-2 antibody complexes show strong biological activity by avoiding interaction with IL-2 receptor α subunit CD25

“…In contrast, JES6-1 anti-mIL-2 mAb produced IL-2/mAb complexes that interacted almost exclusively with immune cells expressing high levels of CD25 along with βγ IL-2R; these CD25-directed complexes, designated IL-2/mAb CD25 complexes, induced selective expansion of CD25 + CD4 + Tregs (8). In addition to IL-2, cytokine/mAb complexes can also be generated using IL-3, IL-4, IL-6, or IL-7, which have been successfully used in various animal models, including viral infections, antitumor responses, autoimmune disease, and graft tolerance (8,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”