Studies on the generation and maintenance of mucosal cytotoxic T lymphocytes against human immunodeficiency virus type 1 Gag in mice.

Abstract

Aspects of the generation and maintenance of mucosal immunity against human immunodeficiency virus type 1 (HIV-1) were examined. Mice were immunized either intranasally or intrarectally with recombinant HIV-1 Gag p24 protein plus cholera toxin. Nasal immunization generated strong nasal IgA responses but low vaginal IgA, whereas rectal immunization yielded good vaginal IgA responses but poor nasal responses. Nasal immunization resulted in strong Gag-specific cytotoxic T lymphocyte (CTL) activity in nasal-associated lymphoid tissue (NALT), posterior cervical lymph nodes (pCLNs), and the spleen, but not in mesenteric lymph nodes (MLNs). Rectal immunization induced weak Gag-specific CTLs in the MLNs only, indicating distinct compartmentalization of the upper and lower mucosa. Combining nasal and rectal immunizations overcame their respective deficiencies. CTL memory after the third nasal immunization was found to persist for up to 6 months in the draining pCLNs, but was gradually lost from the NALT induction site. Analysis of the T cell receptor Vbeta usage of Gag-specific CD8(+) T cells in lymphoid tissues of intranasally immunized mice indicated that the memory CTLs in the pCLNs are generated from a few clones in NALT. The memory CTL clones also appear to be poor killers whereas the NALT clones from which the pCLN clones appear to originate are potent killers. Our results support the view that CTL activity is determined by the level and duration of antigen stimulation and that in NALT, CTLs develop as effector memory T cells with high avidity, whereas the pCLNs sequester the memory T cells with low avidity but longer survival.