Differential Outcome of IL-2/Anti–IL-2 Complex Therapy on Effector and Memory CD8+ T Cells following Vaccination with an Adenoviral Vector Encoding EBV Epitopes

Abstract

IL-2/anti–IL-2 complex-based therapy has been proposed as a potential adjunct therapeutic tool to enhance in vivo efficacy of T cell-based immunotherapeutic strategies for chronic viral infections and human cancers. In this study, we demonstrate that IL-2 complex therapy can have discerning effects on CD8+ T cells depending on their stage of differentiation. To delineate the underlying mechanism for these opposing effects on CD8+ T cells, we examined the effects of IL-2 therapy during early priming, effector, and memory phases of T cell responses generated following immunization with an adenoviral vector encoding multiple EBV CD8+ epitopes. IL-2 complex treatment during the early priming phase, which coincided with low levels of IL-2Rβ (CD122) and higher levels of IL-2Rα (CD25) on CD8+ T cells, did not induce the expansion of effector T cells. In contrast, IL-2 complex treatment following the establishment of memory enhanced the expansion of Ag-specific T cells. Additionally, central memory T cells preferentially expanded following treatment at the expense of effector memory T cell populations. These studies demonstrate how differentiation status of the responding CD8+ T cells impacts on their responsiveness to IL-2 complexes and highlight that timing of treatment should be considered before implementing this therapy in a clinical setting.

Endogenous tumor-reactive CD8+T cells are differentiated effector cells expressing high levels of CD11a and PD-1 but are unable to control tumor growth

“…Murine CD11a high CD8 + T cells include memory CD8 + T cells capable of mounting vigorous recall responses upon a secondary antigenic challenge 12 . Building upon these studies, the elevated expression of CD11a on CD8 + T cells has been used to track antigen-primed effector and memory CD8 + T cells as induced by viral vaccination 13 , 14 . The utility of CD11a for studying antigen-primed CD8 + T cells is demonstrated by the fact that only a portion of CD11a high CD8 + T cells can be detected by MHC Class I tetramer staining, while all corresponding antigen-specific CD8 + T cells reside within the CD11a high CD8 + T-cell population 14 .…”

Optimising IL-2 for Cancer Immunotherapy

“…This finding is perhaps not surprising when it is borne in mind that CD25 expression on T cells varies according to their stage of differentiation, being maximal on effector cells but low on exhausted cells and also memory cells. Here, it is of interest that the capacity of IL-2/S4B6 complexes to expand effector CD8 T cells is quite poor soon after vaccination, i.e, at a stage when the cells are CD25 hi , but improves at later stages when the cells downregulate CD25 along with upregulation of CD122 ( 126 ). This finding raises the question whether CD25 + effector CD8 T cells can be expanded with IL-2/JES6-1 complexes, i.e., in parallel with Tregs.…”

Utility of IL-2 Complexes in Promoting the Survival of Murine Orthotopic Forelimb Vascularized Composite Allografts

“…17–19 Such expansion is sufficient to promote acceptance of murine islet allografts, 19,20 and to suppress murine graft-versus-host disease, 21 whereas IL-2C therapy was much less effective in preventing the rejection of skin allografts. 20 Moreover, IL-2C administration can also promote the proliferation and differentiation of Tcells, especially CD8 Tcells, 22 thereby potentially acting as a “double-edged sword.” 23 Because there are currently no data as to the effects of IL-2C therapy in VCA models, we compared the effects of pre-and post-Tx administration of IL-2C in mice undergoing orthotopic forelimb VCA. The findings of these studies provide new insights into the functions of Treg cells in VCA recipients, and have implications for the ongoing development of strategies to induce long-term VCA survival without maintenance immunosuppression.…”