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.
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-gamma(+) 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-gamma-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.
Belyakov
Igor M
IM
Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. igorbelyakov@yahoo.com
Isakov
Dmitry
D
Zhu
Qing
Q
Dzutsev
Amiran
A
Berzofsky
Jay A
JA
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000285:Administration, Rectal; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology; D002448:Cell Adhesion / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D018928:Immunity, Mucosal; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000821:virology
D016915:AIDS Vaccines; D018449:SAIDS Vaccines; D007371:Interferon-gamma