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Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta, Canada
Although the adaptive immune system has a remarkable ability to mount rapid recall responses to previously encountered pathogens, the cellular and molecular signals necessary for memory CD8+ T cell reactivation are poorly defined. IL-15 plays a critical role in memory CD8+ T cell survival; however, whether IL-15 is also involved in memory CD8+ T cell reactivation is presently unclear. Using artificial Ag-presenting surfaces prepared on cell-sized microspheres, we specifically addressed the role of IL-15 transpresentation on mouse CD8+ T cell activation in the complete absence of additional stimulatory signals. In this study we demonstrate that transpresented IL-15 is significantly more effective than soluble IL-15 in augmenting anti-CD3
-induced proliferation and effector molecule expression by CD8+ T cells. Importantly, IL-15 transpresentation and TCR ligation by anti-CD3 or peptide MHC complexes exhibited synergism in stimulating CD8+ T cell responses. In agreement with previous studies, we found that transpresented IL-15 preferentially stimulated memory phenotype CD8+ T cells; however, in pursuing this further, we found that central memory (TCM) and effector memory (TEM) CD8+ T cells responded differentially to transpresented IL-15. TCM CD8+ T cells undergo Ag-independent proliferation in response to transpresented IL-15 alone, whereas TEM CD8+ T cells are relatively unresponsive to transpresented IL-15. Furthermore, upon Ag-specific stimulation, TCM CD8+ T cell responses are enhanced by IL-15 transpresentation, whereas TEM CD8+ T cell responses are only slightly affected, both in vitro and in vivo. Thus, our findings distinguish the role of IL-15 transpresentation in the stimulation of distinct memory CD8+ T cell subsets, and they also have implications for ex vivo reactivation and expansion of Ag-experienced CD8+ T cells for immunotherapeutic approaches.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by an operating grant from the Canadian Institutes for Health Research (to K.P.K.) and support from the Canadian Network for Vaccines and Immunotherapeutics. K.P.K. is an Alberta Heritage Foundation for Medical Research Scientist. A.I.K. was supported by the Canadian Network for Vaccines and Immunotherapeutics.
2 Address correspondence and reprint requests to Dr. Kevin P. Kane, Department of Medical Microbiology and Immunology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail address: kevin.kane{at}ualberta.ca
3 Abbreviations used in this paper: IL-15R
, IL-15 receptor ; MP, memory phenotype; LCMV, lymphocytic choriomeningitis virus; grB, granzyme B; DC, dendritic cell; pMHC, peptide MHC; TCM, central memory; TEM, effector memory; NP, nucleoprotein.
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