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Memory CD8⁺ T Cell Responses Expand When Antigen Presentation Overcomes T Cell Self-Regulation¹

Ian A. Cockburn^*, Sumana Chakravarty^*, Michael G. Overstreet^*, Adolfo García-Sastre^, and Fidel Zavala^2,*

^* Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; and Department of Microbiology and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029

Antimicrobial memory CD8⁺ T cell responses are not readily expanded by either repeated infections or immunizations. This is a major obstacle to the development of T cell vaccines. Prime-boost immunization with heterologous microbes sharing the same CD8⁺ epitope can induce a large expansion of the CD8⁺ response; however, different vectors vary greatly in their ability to boost for reasons that are poorly understood. To investigate how efficient memory T cell expansion can occur, we evaluated immune regulatory events and Ag presentation after secondary immunization with strong and weak boosting vectors. We found that dendritic cells were essential for T cell boosting and that Ag presentation by these cells was regulated by cognate memory CD8⁺ T cells. When weak boosting vectors were used for secondary immunization, pre-established CD8⁺ T cells were able to effectively curtail Ag presentation, resulting in limited CD8⁺ T cell expansion. In contrast, a strong boosting vector, vaccinia virus, induced highly efficient Ag presentation that overcame regulation by cognate T cells and induced large numbers of memory CD8⁺ T cells to expand. Thus, efficient targeting of Ag to dendritic cells in the face of cognate immunity is an important requirement for T cell expansion.

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 National Institutes of Health Grant AI044375 (to F.Z.) and the National Institutes of Health-funded Center to Investigate Viral Immune Antagonism Grant U19AI62623 (to A.G.-S.).

² Address correspondence and reprint requests to Dr. Fidel Zavala, Department of Molecular Microbiology and Immunology, Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205. E-mail address: fzavala{at}jhsph.edu

³ Abbreviations used in this paper: DC, dendritic cell; Ad-CS, adenovirus-CS; Flu-ME, influenza-ME; -spz, irradiated sporozoites; VV-SYV, vaccinia-SYV; DT, diphtheria toxin.