Differential localization and limited cytotoxic potential of duodenal CD8+ T cells
Leonard Mvaya, Trevor Khaba, Agness E. Lakudzala, Thandeka Nkosi, Ndaru Jambo, Innocent Kadwala, Anstead Kankwatira, Priyanka D. Patel, Melita A. Gordon, Tonney S. Nyirenda, Kondwani C. Jambo, Zaza M. Ndhlovu
Leonard Mvaya, Trevor Khaba, Agness E. Lakudzala, Thandeka Nkosi, Ndaru Jambo, Innocent Kadwala, Anstead Kankwatira, Priyanka D. Patel, Melita A. Gordon, Tonney S. Nyirenda, Kondwani C. Jambo, Zaza M. Ndhlovu
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Research Article AIDS/HIV Immunology

Differential localization and limited cytotoxic potential of duodenal CD8+ T cells

Abstract

The duodenum is a major site of HIV persistence during suppressive antiretroviral therapy despite harboring abundant tissue-resident memory (Trm) CD8+ T cells. The role of duodenal Trm CD8+ T cells in viral control is still not well defined. We examined the spatial localization, phenotype, and function of CD8+ T cells in the human duodenal tissue from people living with HIV (PLHIV) and healthy controls. We found that Trm (CD69+CD103hi) cells were the predominant CD8+ T cell population in the duodenum. Immunofluorescence imaging of the duodenal tissue revealed that CD103+CD8+ T cells were localized in the intraepithelial region, while CD103–CD8+ T cells and CD4+ T cells were mostly localized in the lamina propria (LP). Furthermore, HIV-specific CD8+ T cells were enriched in the CD69+CD103–/lo population. However, the duodenal HIV-specific CD8+ Trm cells rarely expressed canonical molecules for potent cytolytic function (perforin and granzyme B) but were more polyfunctional than those from peripheral blood. Taken together, our results show that duodenal CD8+ Trm cells possess limited perforin-mediated cytolytic potential and are spatially separated from HIV-susceptible LP CD4+ T cells. This could contribute to HIV persistence in the duodenum and provides critical information for the design of cure therapies.

Authors

Leonard Mvaya, Trevor Khaba, Agness E. Lakudzala, Thandeka Nkosi, Ndaru Jambo, Innocent Kadwala, Anstead Kankwatira, Priyanka D. Patel, Melita A. Gordon, Tonney S. Nyirenda, Kondwani C. Jambo, Zaza M. Ndhlovu

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Figure 2

Characterization and spatial localization of resident memory CD4+ and CD8+ T cells in the duodenum.

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Characterization and spatial localization of resident memory CD4+ and CD...
DMNCs from HIV-uninfected adults and PLHIV were stained with fluorochrome-conjugated antibodies against surface markers of interest. FFPE duodenal tissues were used to evaluate spatial localization of CD4+ and CD8+ T cells by immunofluorescence microscopy. (A) Representative flow cytometry plots showing identification of duodenal CD8+ and CD4+ T cells expressing different combinations of CD69 and CD103. (B) Pie charts representing the median proportion of duodenal CD8+ and CD4+ T cells expressing different combinations of CD69 and CD103 in different participant groups (HIV−, n = 13; ART–, n = 13; ART+, n = 10). (C) Representative histogram showing CD103 expression by duodenal CD4+ and CD8+ T cells. (D) CD103 expression intensity in duodenal CD4+ T cells compared with CD8+ T cells in different study participant groups (HIV−, n = 12; ART–, n = 13; ART+, n = 8). Data were analyzed using Kruskal–Wallis test and adjusted for multiple comparisons (2-stage Benjamini, Krieger, & Yekutieli) for different participant groups. (E) Representative IHC image of duodenal biopsy section showing CD8 (green), CD103 (orange), and DAPI (blue) staining within the delineated compartments defined as the IE region and the LP. (F) Representative IHC image of duodenal biopsy section showing CD4 (green), CD103 (orange), and DAPI (blue) staining within the delineated compartments defined as the IE region and the LP (G). (H) Density of CD103 expressing CD4+ and CD8+ T cells within duodenal tissue from PLHIV (ART–, n = 2; ART+, n = 2) and HIV-uninfected individuals (n = 3). Data were analyzed using Wilcoxon’s test (G).