Mucosal-associated invariant T cells predict increased acute graft-versus-host-disease incidence in patients receiving allogeneic hematopoietic stem cell transplantation

Abstract

Background Mucosal-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. Methods The 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. Results Our 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. Conclusions Our 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.

Mucosal-associated invariant T cells are functionally impaired in pediatric and young adult patients following allogeneic hematopoietic stem cell transplantation and their recovery correlates with clinical outcomes

“…S2B). CI of aGvHD and grade II-IV aGvHD did not differ significantly among different types of HSCT: 31% (95%CI 20-45) vs 22% (95%CI [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] and 21% (95%CI 12-35) vs 18% (95%CI 11-28) in MUD and Haplo-HSCT, respectively, p=0.27 and p=0.78). Similar results among the two groups were also observed analyzing cGvHD occurrence: 5 MUD-HSCT and 10 Haplo-HSCT experienced cGvHD (CI 10%, 95%CI 4-22, vs 12%, 95%CI 6-21, respectively, p=0.66), with a CI of moderate/severe cGvHD of 8%, 95%CI 3-20, vs 8%, 95%CI 4-17, respectively, p=0.85.…”

“…An increasing number of studies have investigated the role of MAIT cells during immune reconstitution following allo-HSCT. It has been reported that MAIT cell recovery is primarily graftderived after transplantation and that a higher proportion of MAIT cells in the graft is associated with a greater incidence of acute GvHD (aGvHD) 17,18 . Previous studies also suggested that reduced post-HSCT MAIT cell count is associated with the development of aGvHD [18][19][20] .…”

Graft-versus-Host Disease Modulation by Innate T Cells

“…Innate T cells, as previously noted, do not recognize MHC molecules, reducing GvHD by limiting the detection of foreign antigens by surveilling immune cells. Low frequencies of MAIT, iNKT, and γδ T cells are correlated with an elevated risk of GvHD and a decreased overall survival rate in patients following allogeneic stem cell transplantation, suggesting innate T cells play a role in the modulation of GvHD in recipients of allogeneic transplants [ 28 , 43 , 92 ]. Therefore, these T-cell subtypes are receiving increasing attention to address GvHD in transplant patients.…”

Mucosal-associated invariant T cells in cancer: dual roles, complex interactions and therapeutic potential

“…One distinguishing characteristic that significantly contributes to their therapeutic appeal is their incapacity to induce graft-versus-host disease (GvHD) ( 105 – 107 ). This is attributed to their restriction by MR1 and their non-recognition of mismatched major histocompatibility complex (MHC) molecules and protein autoantigens ( 105 ).…”