Human MAIT cells inhibit alloreactive T cell responses and protect against acute graft-versus-host disease
Nana Talvard-Balland, Marion Lambert, Mathieu F. Chevalier, Norbert Minet, Marion Salou, Marie Tourret, Armelle Bohineust, Idan Milo, Véronique Parietti, Thomas Yvorra, Gérard Socié, Olivier Lantz, Sophie Caillat-Zucman
Nana Talvard-Balland, Marion Lambert, Mathieu F. Chevalier, Norbert Minet, Marion Salou, Marie Tourret, Armelle Bohineust, Idan Milo, Véronique Parietti, Thomas Yvorra, Gérard Socié, Olivier Lantz, Sophie Caillat-Zucman
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Research Article Immunology Transplantation

Human MAIT cells inhibit alloreactive T cell responses and protect against acute graft-versus-host disease

Abstract

Adoptive transfer of immunoregulatory cells can prevent or ameliorate graft-versus-host disease (GVHD), which remains the main cause of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation. Mucosal-associated invariant T (MAIT) cells were recently associated with tissue repair capacities and with lower rates of GVHD in humans. Here, we analyzed the immunosuppressive effect of MAIT cells in an in vitro model of alloreactivity and explored their adoptive transfer in a preclinical xenogeneic GVHD model. We found that MAIT cells, whether freshly purified or short-term expanded, dose-dependently inhibited proliferation and activation of alloreactive T cells. In immunodeficient mice injected with human PBMCs, MAIT cells greatly delayed GVHD onset and decreased severity when transferred early after PBMC injection but could also control ongoing GVHD when transferred at delayed time points. This effect was associated with decreased proliferation and effector function of human T cells infiltrating tissues of diseased mice and was correlated with lower circulating IFN-γ and TNF-α levels and increased IL-10 levels. MAIT cells acted partly in a contact-dependent manner, which likely required direct interaction of their T cell receptor with MHC class I–related molecule (MR1) induced on host-reactive T cells. These results support the setup of clinical trials using MAIT cells as universal therapeutic tools to control severe GVHD or mucosal inflammatory disorders.

Authors

Nana Talvard-Balland, Marion Lambert, Mathieu F. Chevalier, Norbert Minet, Marion Salou, Marie Tourret, Armelle Bohineust, Idan Milo, Véronique Parietti, Thomas Yvorra, Gérard Socié, Olivier Lantz, Sophie Caillat-Zucman

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Figure 2

The inhibitory effect of MAIT cells on alloreactive T cells is partially contact dependent, requires TCR-MR1 interaction, and leads to inhibition of alloreactive T cell activation.

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The inhibitory effect of MAIT cells on alloreactive T cells is partially...
(A) Responder CFSE-labeled CD4+ T cells with stimulator allogeneic CD3– PBMCs, and MAIT cells (or CD8EM) at a 1:2 MAIT/CD4+ T cell ratio, were cultured in the upper and/or lower chamber of a Transwell plate, as indicated for each condition. Percentage (mean ± SEM) of inhibition of responder T cell proliferation (versus “condition 1” as reference) is shown for each culture setting. (B) Representative MR1 expression on responder CD4+ T cells at baseline (D0) and D6 of the MLR (where indicated, 5-OP-RU or Ac-6-FP was used to stabilize MR1 surface expression). (C) Human alloreactive (CFSE–) or nonalloreactive (CFSE+) human CD4+ T cells were sorted (at day 6 of the MLR) and cocultured with murine MAIT “reporter” cells obtained by isolating splenocytes from double-transgenic mice (Vα19 and Vβ8 TCR, Cα–/–, MR1–/–). After 16 hours in the absence or presence of 5-OP-RU (100 nM), expression of CD69 and CD25 was measured on murine MAIT reporter cells (MR1-tetramer+ T cells). (D) Percentage inhibition (mean ± SEM) of responder CD4+ T cell proliferation by MAIT cells (1:2 ratio) in the absence or presence of the inhibitory MR1 ligand Ac-6-FP at indicated concentrations. (E) Expression of Nur77 transcription factor in responder CD4+ T cells at D6 of the MLR. (F) Expression level (mean %, ± SEM) of indicated markers as assessed by spectral cytometry on responder CD4+ T cells on day 6 of the MLR in the absence (Ctrl) or presence of MAIT cells (1:2 ratio) alone or with Ac-6-FP (1 μM). (G) Percentage inhibition (mean ± SEM) of responder CD4+ T cell proliferation by MAIT cells (1:2 ratio) in the absence or presence of the activating MR1 ligand 5-OP-RU at indicated concentrations. Results are representative of at least of 3 independent experiments. *P 0.05, **P 0.01, ***P 0.001, ****P 0.001, from paired t tests or 1-way ANOVA followed by Tukey’s multiple comparisons test (A) or followed by Dunnett’s (D, F, and G).