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Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8⁺ T Cells of the Effector (CD44^highCD62L^low) and Central (CD44^highCD62L^high) Phenotype by an Archaeosome Adjuvant Independent of TLR2¹

Lakshmi Krishnan^2,*,, Komal Gurnani^*, Chantal J. Dicaire^*, Henk van Faassen^*, Ahmed Zafer^*, Carsten J. Kirschning, Subash Sad^*, and G. Dennis Sprott^*

^* National Research Council-Institute for Biological Sciences, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada; and Institute for Microbiology, Immunology, and Hygiene, Technical University, Munich, Germany

Vaccines capable of eliciting long-term T cell immunity are required for combating many diseases. Live vectors can be unsafe whereas subunit vaccines often lack potency. We previously reported induction of CD8⁺ T cells to Ag entrapped in archaeal glycerolipid vesicles (archaeosomes). In this study, we evaluated the priming, phenotype, and functionality of the CD8⁺ T cells induced after immunization of mice with OVA-Methanobrevibacter smithii archaeosomes (MS-OVA). A single injection of MS-OVA evoked a profound primary response but the numbers of H-2K^bOVA_257–264-specific CD8⁺ T cells declined by 14–21 days, and <1% of primarily central phenotype (CD44^highCD62L^high) cells persisted. A booster injection of MS-OVA at 3–11 wk promoted massive clonal expansion and a peak effector response of 20% splenic/blood OVA_257–264-specific CD8⁺ T cells. Furthermore, contraction was protracted and the memory pool (IL-7R^high) of 5% included effector (CD44^highCD62L^low) and central (CD44^highCD62L^high) phenotype cells. Recall response was observed even at >300 days. CFSE-labeled naive OT-1 (OVA_257–264 TCR transgenic) cells transferred into MS-OVA-immunized recipients cycled profoundly (>90%) within the first week of immunization indicating potent Ag presentation. Moreover, 25% cycling of Ag-specific cells was seen for >50 days, suggesting an Ag depot. In vivo, CD8⁺ T cells evoked by MS-OVA killed >80% of specific targets, even at day 180. MS-OVA induced responses similar in magnitude to Listeria monocytogenes-OVA, a potent live vector. Furthermore, protective CD8⁺ T cells were induced in TLR2-deficient mice, suggesting nonengagement of TLR2 by archaeal lipids. Thus, an archaeosome adjuvant vaccine represents an alternative to live vectors for inducing CD8⁺ T cell memory.

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 funds from the Ontario Cancer Research Institute and the National Research Council (NRC) of Canada. This is NRC Publication Number 42512.

² Address correspondence and reprint requests to Dr. Lakshmi Krishnan, National Research Council-Institute for Biological Sciences, 1200 Montreal Road, Building M-54, Ottawa, Ontario, Canada. E-mail address: Lakshmi.Krishnan{at}nrc-cnrc.gc.ca

³ Abbreviations used in this paper: DC, dendritic cell; MS, Methanobrevibacter smithii; PS, phosphatidylserine; TPL, total polar lipid; LM, Listeria monocytogenes; PAMP, pathogen-associated molecular pattern; T_E, effector T cell; T_EM, effector memory T cell; T_CM, central memory T cell; PRR, pathogen-recognition receptor.

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