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. 2019 Jan;49(1):133-143.
doi: 10.1002/eji.201847759. Epub 2018 Nov 14.

Tissue-resident MAIT cell populations in human oral mucosa exhibit an activated profile and produce IL-17

Michał J Sobkowiak  1 , Haleh Davanian  2 , Robert Heymann  2   3 , Anna Gibbs  4 , Johanna Emgård  1 , Joana Dias  1 , Soo Aleman  5 , Carina Krüger-Weiner  2 , Markus Moll  1 , Annelie Tjernlund  4 , Edwin Leeansyah  1   6 , Margaret Sällberg Chen  2 , Johan K Sandberg  1
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Tissue-resident MAIT cell populations in human oral mucosa exhibit an activated profile and produce IL-17

Michał J Sobkowiak et al. Eur J Immunol. 2019 Jan.

Abstract

Mucosa-associated invariant T (MAIT) cells are unconventional T lymphocytes defined by their innate-like characteristics and broad antimicrobial responsiveness. Whether MAIT cells are part of the tissue-resident defense in the oral mucosal barrier is unknown. Here, we found MAIT cells present in the buccal mucosa, with a tendency to cluster near the basement membrane, and located in both epithelium and the underlying connective tissue. Overall MAIT cell levels were similar in the mucosa compared to peripheral blood, in contrast to conventional T cells that showed an altered representation of CD4+ and CD8+ subsets. The major mucosal MAIT cell subset displayed a tissue-resident and activated profile with high expression of CD69, CD103, HLA-DR, and PD-1, as well as a skewed subset distribution with higher representation of CD4- /CD8- double-negative cells and CD8αα+ cells. Interestingly, tissue-resident MAIT cells had a specialized polyfunctional response profile with higher IL-17 levels, as assessed by polyclonal stimulus and compared to tissue nonresident and circulating populations. Furthermore, resident buccal MAIT cells were low in perforin. Together, these data indicate that MAIT cells form a part of the oral mucosal T cell compartment, where they exhibit a tissue-resident-activated profile biased toward IL-17 production. VSports手机版.

Keywords: Buccal mucosa; IL-17; MAIT cells; MR1; Oral mucosa; Tissue residency. V体育安卓版.

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Conflict of interest statement (VSports)

J. K VSports最新版本. S. , E. L. , and M. S. C. conceived the original research idea and study design.

M. J. S. , H. D. , M. M. , A V体育平台登录. T. , J. D. , E. L. , M. S. C. , and J. K. S. designed experiments.

M. J VSports注册入口. S. , H. D, A. G. , and J. E. conducted experiments.

M. J. S. , H. D. , and A. G V体育官网入口. analyzed experimental data.

R. H. , S. A. , and C VSports在线直播. K. W. recruited study volunteers and collected essential human samples.

M.J.S. and J.K.S. wrote the manuscript.

All authors reviewed and commented on the manuscript.

The authors declare no commercial or financial conflict of interest.

Figures

Figure 1
Figure 1
MAIT cells are part of the oral buccal mucosa T cell compartment. (A) Gating strategy to identify T cell populations in buccal mucosa by flow cytometry. (B) Representative staining of identification of MR1:5‐OP‐RU tetramer binding CD161+ MAIT cells within the CD3+Vα7.2+ buccal mucosal cell population (upper panels), and identification of CD161+Vα7.2+ MAIT cells within the MR1:5‐OP‐RU tetramer binding CD3+ buccal mucosal cell population (lower panels). (C) Comparison of T‐cell subset frequency in peripheral blood and buccal mucosa. All numbers given as percentage of CD3+ lymphocytes (n = 55 [MAIT], 32 [others]). (D) Location of MAIT cells within the buccal mucosa. Representative bright field image of buccal mucosal tissue section, from a healthy donor, stained for Vα7.2 in brown (DAB) and IL‐18Rα in green (Vina Green) showing that the MAIT cells are localized close to the basement membrane (n = 6). The images on the right, collected with a 100× objective, are magnified view of the region indicated in the box in the image to the left, collected with a 40× objective. The scale bar represents 60 μm, image including epithelium (EP) and connective tissue (CT). Representative immunofluorescence images of buccal mucosal tissue sections, from a healthy individual, stained for (E) MR1 (red) and HLA‐DR (green) and stained for (F) Vα7.2 (red) and CD3 (green). Double‐positive cells appear as yellow, arrows point to double‐positive cells for each marker combination. DAPI (blue) was used as a counterstain for visualization of cell nuclei. The images were collected with 40× objective. For each panel, "n" indicates the number of individual human donors tested for each dataset. Statistical significance determined using Wilcoxon matched pairs test for paired data. ***p <0.001, ****p <0.0001.
Figure 2
Figure 2
Co‐receptor and TCR‐Jα usage differences between blood and buccal mucosal MAIT cells. (A) Representation of MAIT cell subsets defined by CD4+ and CD8+ expression. All numbers given as percentage of Vα7.2+CD161+ cells (n = 32). (B) Representative flow cytometric plots of CD8α and CD8β expression in T cell subsets in blood and mucosa. (C) Comparison of CD8αα expression in CD8+ T cell subsets in blood and mucosa. All numbers given as percentage of CD8+ cells (n = 25). (D) Percentage MAIT cells among the mucosa CD8αα+ T‐cell population (n = 23). In C and D, medians and interquartile ranges are indicated. (E) MAIT cell TCR Jα segment usage in paired blood and mucosal samples from healthy donors (n = 6). For each panel, "n" indicates the number of individual human donors tested. Statistical significance determined using Wilcoxon matched pairs test for paired data. ***p <0.001, ****p <0.0001.
Figure 3
Figure 3
Buccal mucosal MAIT cells express PLZF and exhibit an activated PD‐1+ phenotype. (A) Representative histograms of HLA‐DR and CD38 expression in oral buccal mucosa T cell subsets. (B) Representative FACS plot of CD38 and HLA‐DR coexpression in buccal MAIT cells. (C) Expression of HLA‐DR (n = 34), CD38 (n = 12), and PD‐1 (n = 12) in blood and mucosal MAIT cells, as percentage of or mean fluorescence intensity (MFI) in Vα7.2+CD161+ cells. (D) Intracellular staining histograms of PLZF, perforin and granulysin in buccal T cell subsets. (E) Expression levels of PLZF (n = 32), perforin (n = 29), and granulysin (n = 17) in blood and oral mucosal MAIT cells, as MFI in Vα7.2+CD161+ cells. For each panel, "n" indicates the number of individual human donors tested. Statistical significance determined using Wilcoxon matched pairs test for paired data. **p< 0.01, ***p< 0.001, ****p< 0.0001.
Figure 4
Figure 4
Tissue resident and nonresident MAIT cells in buccal mucosa. (A) Representative plot of CD69 and CD103 expression in buccal MAIT cells. (B) Expression of CD69 (n = 25) and CD103 (n = 8) in blood and mucosal MAIT cells, and expression of CD69 in mucosal CD103+ and CD103– MAIT cells (n = 7). (C) Expression of CD4+ and CD8+ in blood MAIT cells, and subsets of buccal MAIT cells defined by CD69 and CD103. Proportion of each marker given as median value (n = 6). (D) CD4+ and CD8+ expression profile in mucosal CD103+ and CD103– MAIT cells (n = 7). (E) Expression of HLA‐DR (n = 8) and CD38 (n = 6) in mucosal CD103+ and CD103– MAIT cells. (F) Expression of PLZF and perforin in mucosal CD103+ and CD103– MAIT cells (n = 6). For each panel, "n" indicates the number of individual human donors tested. Statistical significance determined using Wilcoxon matched pairs test for paired data. *p <0.05, **p <0.01, ****p< 0.0001.
Figure 5
Figure 5
Functional profile of MAIT cells in buccal mucosa and blood. (A) Representative histograms of intracellular staining for TNF, IFN‐γ, IL‐2, IL‐17A, and granzyme B in CD103+ and CD103– MAIT cells from buccal mucosa, in comparison with blood MAIT cells after stimulation with PMA/ionomycin. (B) Expression of cytokines by MAIT cells from blood and buccal mucosa of healthy donors after PMA/ionomycin stimulation (n = 7). (C) Total level of activation of MAIT cells from blood or mucosa after PMA/ionomycin stimulation, defined as percentage of total MAIT cells, which express at least one of the factors TNF, IFN‐γ, IL‐2, IL‐17A, and granzyme B (n = 6). (C) Medians and interquartile ranges are indicated. (D) Overall polyfunctionality of blood, CD103–, and CD103+ mucosal MAIT cells. Percentages represent the mean of values from a set of donors (n = 6). (E) Polyfunctional response profile of activated MAIT cells from blood, as well as CD103– and CD103+ mucosal MAIT cells (n = 6). For each panel, "n" indicates the number of individual human donors tested. Statistical significance determined using Wilcoxon matched pairs test for paired data. *p <0.05, **p <0.01.
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References

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