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

Martin Solders,Mats Remberger,Helen Kaipe,Laia Gorchs,Tom Erkers,Isabelle Magalhaes,Thomas Poiret

doi:10.3389/fimmu.2017.01861

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+CD161dim/negTCRVα7.2dim/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-γ 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.

Highlights

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for hematological malignancies [1, 2], immunodeficiencies, and some inborn errors of metabolism [2, 3]
When analyzing secreted levels of granzyme B (GrzB) from Peripheral blood mononuclear cells (PBMCs), we found that GrzB was not significantly released upon E. coli stimulation in samples acquired up to 6 months post HSCT, whereas the 24-month patient samples responded compared to healthy controls (HC) (Figure 3E)
Systemic Mucosal-associated invariant T (MAIT) cell deficiency have been correlated with severe systemic diseases such as tuberculosis [19, 34], hepatitis C [35], and HIV [36], and with septic as well as non-septic critically ill patients [37]

Summary

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for hematological malignancies [1, 2], immunodeficiencies, and some inborn errors of metabolism [2, 3]. The innate immune system is reconstituted during the first months after HSCT, but it takes years to develop a competent adaptive immune system [7]. During this time, the patients are at higher risk of acquiring opportunistic infections. T cells from the transplanted graft are a vital part of the adaptive immune cell compartment of HSCT patients during the first year after transplantation, with a reduced TCR repertoire diversity [8]. New T-cells differentiate from the transplanted stem cells in measurable amounts after approximately 3 months following HSCT [10]. If the patients experience complications such as GvHD, relapse or infection by LPS-producing bacteria, or CMV, the immune reconstitution is hampered further [11, 13,14,15]

Methods

Results

Conclusion