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HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women.

Musey L, Hu Y, Eckert L, Christensen M, Karchmer T, McElrath MJ - J. Exp. Med. (1997)

Bottom Line: Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1.Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids.Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The University of Washington School of Medicine, Seattle 98195, USA.

ABSTRACT
Although T lymphocytes are present in the genital mucosa, their function in sexually transmitted diseases is unproven. To determine if cervical T cells mediate HIV-specific cytolysis, mononuclear cells in cytobrush specimens from HIV-1-infected women were stimulated in vitro with antigen. Resultant cell lines lysed autologous targets expressing HIV-1 proteins in 12/19 (63%) subjects, and these responses were detected intermittently on repeated visits. All 8 subjects with blood CD4+ counts > or =500 cells/microl had HIV-1-specific cervical CTL, whereas only 4/11 with counts <500 cells/microl had detectable responses (P = 0.008). Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1. Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids. Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood. These studies provide the first definitive evidence for an MHC-restricted effector function in human cervical lymphocytes.

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Gag-specific CTL clones from the cervix and blood of Subject 710 are HLA class I restricted. Gag-specific clones were tested for lysis of B-LCL infected with vDK-1 (Gag) or vSC-8 (control). Class I  MHC-restricted lysis by the clones is evidenced by lysis of the Gagexpressing autologous B-LCL (A24,B14,B27) and B-LCL from donors  sharing one class I HLA allele as indicated on the figure. Lysis of the control targets infected with vSC-8 (vac-lac) were <2% for all targets. (A)  Three cervical CTL clones from visit 8, tested at an E/T of 3:1. (B) Six  cervical CTL clones from visit 11, tested at an E/T of 5:1. (C) Four  PBMC-derived CTL clones from visit 8, tested at an E/T of 4:1.
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Figure 5: Gag-specific CTL clones from the cervix and blood of Subject 710 are HLA class I restricted. Gag-specific clones were tested for lysis of B-LCL infected with vDK-1 (Gag) or vSC-8 (control). Class I MHC-restricted lysis by the clones is evidenced by lysis of the Gagexpressing autologous B-LCL (A24,B14,B27) and B-LCL from donors sharing one class I HLA allele as indicated on the figure. Lysis of the control targets infected with vSC-8 (vac-lac) were <2% for all targets. (A) Three cervical CTL clones from visit 8, tested at an E/T of 3:1. (B) Six cervical CTL clones from visit 11, tested at an E/T of 5:1. (C) Four PBMC-derived CTL clones from visit 8, tested at an E/T of 4:1.

Mentions: Patient 710 had a vigorous Env- and Gag-specific CTL response during the majority of monthly visits (Fig. 2). To determine the breadth of CD8+ CTL epitope specificity, we chose to clone the Gag-specific cervical CTL lines from visits 8 and 11. Three CD8+ CTL clones derived from the cytobrush specimen taken on visit 8 (Fig. 1 B) and six clones from visit 11 demonstrated lytic activity to Gag-expressing autologous B-LCL (Table 3). As shown in Fig. 5, A and B, lytic activity of these CD8+ clones was restricted by either class I HLA-B14 or HLA-B27. All cervical-derived clones recognized targets expressing Gag epitopes within the p24 region: the B14-restricted clones lysed targets pulsed with the 20-mer spanning aa 290-309, and the B27-restricted clones, the 20-mer spanning aa 160-179 (Table 3). Thus, the patterns of gag epitope recognition in the cervical mucosa were consistent in the two time periods separated by a four month interval.


HIV-1 induces cytotoxic T lymphocytes in the cervix of infected women.

Musey L, Hu Y, Eckert L, Christensen M, Karchmer T, McElrath MJ - J. Exp. Med. (1997)

Gag-specific CTL clones from the cervix and blood of Subject 710 are HLA class I restricted. Gag-specific clones were tested for lysis of B-LCL infected with vDK-1 (Gag) or vSC-8 (control). Class I  MHC-restricted lysis by the clones is evidenced by lysis of the Gagexpressing autologous B-LCL (A24,B14,B27) and B-LCL from donors  sharing one class I HLA allele as indicated on the figure. Lysis of the control targets infected with vSC-8 (vac-lac) were <2% for all targets. (A)  Three cervical CTL clones from visit 8, tested at an E/T of 3:1. (B) Six  cervical CTL clones from visit 11, tested at an E/T of 5:1. (C) Four  PBMC-derived CTL clones from visit 8, tested at an E/T of 4:1.
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Related In: Results  -  Collection

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Figure 5: Gag-specific CTL clones from the cervix and blood of Subject 710 are HLA class I restricted. Gag-specific clones were tested for lysis of B-LCL infected with vDK-1 (Gag) or vSC-8 (control). Class I MHC-restricted lysis by the clones is evidenced by lysis of the Gagexpressing autologous B-LCL (A24,B14,B27) and B-LCL from donors sharing one class I HLA allele as indicated on the figure. Lysis of the control targets infected with vSC-8 (vac-lac) were <2% for all targets. (A) Three cervical CTL clones from visit 8, tested at an E/T of 3:1. (B) Six cervical CTL clones from visit 11, tested at an E/T of 5:1. (C) Four PBMC-derived CTL clones from visit 8, tested at an E/T of 4:1.
Mentions: Patient 710 had a vigorous Env- and Gag-specific CTL response during the majority of monthly visits (Fig. 2). To determine the breadth of CD8+ CTL epitope specificity, we chose to clone the Gag-specific cervical CTL lines from visits 8 and 11. Three CD8+ CTL clones derived from the cytobrush specimen taken on visit 8 (Fig. 1 B) and six clones from visit 11 demonstrated lytic activity to Gag-expressing autologous B-LCL (Table 3). As shown in Fig. 5, A and B, lytic activity of these CD8+ clones was restricted by either class I HLA-B14 or HLA-B27. All cervical-derived clones recognized targets expressing Gag epitopes within the p24 region: the B14-restricted clones lysed targets pulsed with the 20-mer spanning aa 290-309, and the B27-restricted clones, the 20-mer spanning aa 160-179 (Table 3). Thus, the patterns of gag epitope recognition in the cervical mucosa were consistent in the two time periods separated by a four month interval.

Bottom Line: Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1.Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids.Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, The University of Washington School of Medicine, Seattle 98195, USA.

ABSTRACT
Although T lymphocytes are present in the genital mucosa, their function in sexually transmitted diseases is unproven. To determine if cervical T cells mediate HIV-specific cytolysis, mononuclear cells in cytobrush specimens from HIV-1-infected women were stimulated in vitro with antigen. Resultant cell lines lysed autologous targets expressing HIV-1 proteins in 12/19 (63%) subjects, and these responses were detected intermittently on repeated visits. All 8 subjects with blood CD4+ counts > or =500 cells/microl had HIV-1-specific cervical CTL, whereas only 4/11 with counts <500 cells/microl had detectable responses (P = 0.008). Class II MHC-restricted CD4+ CTL clones lysed targets expressing Env gp41 or infected with HIV-1. Class I MHC-restricted CD8+ clones recognized HIV-1 Gag- or Pol-expressing targets, and the epitopes were mapped to within 9-20 amino acids. Comparisons of intra-individual cervical and blood CTL specificities indicate that epitopes recognized by CTL in the cervix were commonly recognized in the blood. These studies provide the first definitive evidence for an MHC-restricted effector function in human cervical lymphocytes.

Show MeSH
Related in: MedlinePlus