SIV-specific CD8+ T cells are enriched in female genital mucosa of rhesus macaques and express receptors for inflammatory chemokines

Abstract

Problem: Mucosal T lymphocyte responses in the female reproductive tract, the primary site of HIV transmission in women, may be critical for initial control of virus infection. In addition, characterization of genital immune responses to HIV will be important for the development of a vaccine capable of preventing infection by this route.

Method of study: We analyzed lymphocytes isolated from vagina and cervix of chronically SIV-infected macaques for the frequency of SIV Gag tetramer-binding cells and expression of chemokine receptors.

Results: We found that the frequency of SIV-specific CD8+ T cell responses was 3- to 30-fold higher in genital tissues than in peripheral blood. SIV-specific CD8+ T cells in genital tissues expressed high levels of CXCR3 and CCR5, chemokine receptors normally expressed on memory T cells that home to inflamed tissues. Cells expressing CXCR3 colocalized with its chemokine ligand CXCL9 [monokine induced by interferon gamma, MIG] in the vaginal lamina propria.

Conclusion: These results indicate that the frequency of SIV-specific CD8+ T cells in the female genital mucosa is enriched compared with peripheral blood and provide initial information regarding the signals that direct recruitment of T cells to the female reproductive tract.

Figure 1. Macaques infected with attenuated SIV strains have higher frequencies of SIV-specific CD8+ T cells in vagina than in peripheral blood

Mononuclear cells isolated from blood and vaginal biopsies were stained with anti-CD3 and anti-CD8 antibodies and Mamu-A*01/SIV Gag_181–189 tetramers. The percentage of tetramer-positive cells was determined for CD3⁺CD8⁺ cells after gating on lymphocytes. A minimum of 10,000 lymphocyte gated events were analyzed for each specimen.

Figure 2. Differential expression of CXCR3 and CCR5 on SIV-specific CD8⁺ T cells in blood and vagina

A. Expression of chemokine receptors on CD8⁺ T cells in the blood and vagina of a SIV-infected macaque. The percentage of all CD8⁺ T cells expressing either the indicated chemokine receptor, Gag tetramer, or both is indicated in the appropriate quadrant. B. Histograms of expression of chemokine receptors on total CD8⁺ T cells (solid blue) or Gag tetramer⁺ cells (red line).

Figure 3. The chemokine receptor CXCR3 and chemokine CXCL9 (MIG) are expressed by cells in vaginal epithelium and in a lymphoid aggregate in the lamina propria of a SIV-infected macaque

Immunohistochemical staining was performed on paraffin-fixed tissues.