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A Novel Functional CTL Avidity/Activity Compartmentalization to the Site of Mucosal Immunization Contributes to Protection of Macaques against Simian/Human Immunodeficiency Viral Depletion of Mucosal CD4⁺ T Cells

Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

The presence of high-avidity CTLs in the right compartment can greatly affect clearance of a virus infection (for example, AIDS viral infection of and dissemination from mucosa). Comparing mucosal vs systemic immunization, we observed a novel compartmentalization of CTL avidity and proportion of functionally active Ag-specific CD8⁺ T cells to tissues proximal to sites of immunization. Whereas both s.c. and intrarectal routes of immunization induced tetramer⁺ cells in the spleen and gut, the mucosal vaccine induced a higher percentage of functioning IFN-⁺ Ag-specific CD8⁺ T cells in the gut mucosa in mice. Translating to the CD8⁺ CTL avidity distribution in rhesus macaques, intrarectal vaccination induced more high-avidity mucosal CTL than s.c. vaccination and protection of mucosal CD4⁺ T cells from AIDS viral depletion, whereas systemic immunization induced higher avidity IFN--secreting cells in the draining lymph nodes but no protection of mucosal CD4⁺ T cells, after mucosal challenge with pathogenic simian/human immunodeficiency virus. Mucosal CD4⁺ T cell loss is an early critical step in AIDS pathogenesis. The preservation of CD4⁺ T cells in colonic lamina propria and the reduction of virus in the intestine correlated better with high-avidity mucosal CTL induced by the mucosal AIDS vaccine. This preferential localization of high-avidity CTL may explain previous differences in vaccination results and may guide future vaccination strategy.

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 Address correspondence and reprint requests to Dr. Igor M. Belyakov, Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. E-mail address: igorbelyakov{at}yahoo.com

² Abbreviations used in this paper: IR, intrarectal; SHIV, simian/human immunodeficiency virus; GALT, gut-associated lymphoid tissue; DC, dendritic cell; LP, lamina propria; MVA, modified vaccinia Ankara; NASBA, nucleic acid sequence-based amplification; IEL, intraepithelial lymphocyte; LPL, LP lymphocyte; MLN, mesenteric lymph node; ALN, axillary lymph node; LT, labile toxin.

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