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Mucosal-Associated Invariant T Cells Display a Poor Reconstitution and Altered Phenotype after Allogeneic Hematopoietic Stem Cell Transplantation.

ABSTRACT: Mucosal-associated invariant T (MAIT) cells are innate-like T cells which are important in the defense against certain bacteria and yeast. The reconstitution of MAIT cells after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We investigated MAIT cell phenotype and function in 17 patients devoid of relapse and severe graft-versus-host disease (GvHD) in paired samples collected 1-2, 3-6, 12, and 24?months after transplantation. Data were compared to 17 healthy controls (HC), as well as 22 patients with acute GvHD grade 2-3. The frequency of MAIT cells within CD3⁺ cells was approximately 10-fold lower than in HC and did not increase over the 2?years following HSCT. MAIT cells in HSCT patients displayed an elevated expression of CD69 and intracellular granzyme B and were predominantly composed of CD4/CD8 double-negative cells. The expression of PD-1 on MAIT cells was low and did not change during the observational time, whereas the CD3⁺CD161^dim/negTCRV?7.2^dim/neg cells (non-MAIT T cells) displayed a high expression early after HSCT that decreased to normal levels at 24?months. MAIT cells collected 2-6?months post-HSCT showed an impaired IFN-? and perforin response after bacterial stimulation, but the response was restored at 24?months. Patients with acute GvHD had similar proportions of MAIT cells as patients with grade 0-1, but consisted mainly of CD8⁺ cells. Finally, MAIT cells were more sensitive to cyclosporine A and sirolimus than non-MAIT T cells. To conclude, MAIT cell reconstitution following HSCT is deficient compared to non-MAIT T cells and GvHD grade ?2 is not correlated with MAIT cell frequency. MAIT cell functionality was impaired early after HSCT, but restored at 24?months post-HSCT. MAIT cells have an increased sensibility to common immunosuppressive drugs, which maybe could explain their hampered reconstitution after HSCT.

SUBMITTER: Solders M

PROVIDER: S-EPMC5742569 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Mucosal-Associated Invariant T Cells Display a Poor Reconstitution and Altered Phenotype after Allogeneic Hematopoietic Stem Cell Transplantation.

Solders Martin M Erkers Tom T Gorchs Laia L Poiret Thomas T Remberger Mats M Magalhaes Isabelle I Kaipe Helen H

Frontiers in immunology 20171221

Mucosal-associated invariant T (MAIT) cells are innate-like T cells which are important in the defense against certain bacteria and yeast. The reconstitution of MAIT cells after allogeneic hematopoietic stem cell transplantation (HSCT) is not known. We investigated MAIT cell phenotype and function in 17 patients devoid of relapse and severe graft-versus-host disease (GvHD) in paired samples collected 1-2, 3-6, 12, and 24 months after transplantation. Data were compared to 17 healthy controls (HC ...[more]

PMID: 29312341

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Project description:BackgroundMucosal-associated invariant T (MAIT) cells are innate-like T cells, some studies have reported that the number of circulating MAIT cells reduced in patients with acute graft-versus-host-disease (aGVHD) development. However, the role of donor MAIT cells on aGVHD development and subsequent functional change still remain unclear.MethodsThe study recruited 86 patients with hematological malignancies who underwent allogeneic hematopoietic cell transplantation (HCT) from May 1, 2018 to June 30, 2019. MAIT cells, their subset, and cytokine levels were measured by flow cytometry. Gray's test was used to assess the impact of graft MAIT cell proportion and number on aGVHD incidence. The Cox proportional hazard model was used in the multivariate analysis. The comparison for continuous variables was assessed using Mann-Whitney analysis. RNA-sequencing was performed to investigate the possible molecular pathway changes.ResultsOur study showed that the proportion of MAIT cells in grafts was not different from normal controls, but the CD4/8 subsets were altered. Taking the median of the proportion and number of MAIT cells in the graft as the threshold, the results showed that the incidence of grade B-D aGVHD in patients with MAIT cell proportion ≥ 3.03% was significantly higher than that in patients with MAIT cell proportion < 3.03% (56.3%, 95% CI 37.1-71.2 versus 23.1%, 95% CI 13.8-46.2; P = 0.038).The number of MAIT cells in the graft was not associated with aGVHD development (P = 0.173), however, when the graft contained more CD4 positive, CD8 positive, and CD4/CD8 double-positive MAIT cells, the incidence of aGVHD was significantly increased (P = 0.019, P = 0.035 and P = 0.027, respectively). Besides, reduced frequencies and counts of circulating MAIT cells were observed in patients with aGVHD when compared to patients without aGVHD, accompanied by enhanced production of Tumor necrosis factor-α, Interferon-γ and upregulated programmed death-1, CXC Chemokine Receptor-6 (CXCR6) and CD38 expression. Gene set enrichment analysis of MAIT cell RNA-seq data showed interferon-α response pathway upregulated in aGVHD patients when compared with patients without aGVHD and healthy controls.ConclusionsOur study shows that MAIT cells in grafts and peripheral blood are both closely related to the aGVHD development post allogeneic HCT. Interferon-α response pathway perhaps is a critical regulation mechanism for the MAIT cell involvement in aGVHD development.

Dataset Information

Mucosal-Associated Invariant T Cells Display a Poor Reconstitution and Altered Phenotype after Allogeneic Hematopoietic Stem Cell Transplantation.

Publications

Mucosal-Associated Invariant T Cells Display a Poor Reconstitution and Altered Phenotype after Allogeneic Hematopoietic Stem Cell Transplantation.

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