MAIT and Vδ2 unconventional T cells are supported by a diverse intestinal microbiome and correlate with favorable patient outcome after allogeneic HCT

Abstract

Microbial diversity is associated with improved outcomes in recipients of allogeneic hematopoietic cell transplantation (allo-HCT), but the mechanism underlying this observation is unclear. In a cohort of 174 patients who underwent allo-HCT, we demonstrate that a diverse intestinal microbiome early after allo-HCT is associated with an increased number of innate-like mucosal-associated invariant T (MAIT) cells, which are in turn associated with improved overall survival and less acute graft-versus-host disease (aGVHD). Immune profiling of conventional and unconventional immune cell subsets revealed that the prevalence of Vδ2 cells, the major circulating subpopulation of γδ T cells, closely correlated with the frequency of MAIT cells and was associated with less aGVHD. Analysis of these populations using both single-cell transcriptomics and flow cytometry suggested a shift toward activated phenotypes and a gain of cytotoxic and effector functions after transplantation. A diverse intestinal microbiome with the capacity to produce activating ligands for MAIT and Vδ2 cells appeared to be necessary for the maintenance of these populations after allo-HCT. These data suggest an immunological link between intestinal microbial diversity, microbe-derived ligands, and maintenance of unconventional T cells.

The contribution of the intestinal microbiome to immune recovery after HCT

“…A higher than median MAIT cell frequency at day 30 post-transplant was correlated with OS and decreased NRM. An association between MAIT frequency and lowered incidence of grades 2 to 4 aGVHD as well as GI GVHD was also seen ( 59 ). Prior to our study, Bhattacharyya et al ( 58 ) had observed that increases in absolute MAIT cell count (in increments as small as 10 MAIT cells/μL) in the blood in the early post-HCT period were associated with a reduced risk of GVHD in a cohort of 105 patients.…”

“…In humans, MAIT cells represent up to 10% of all circulating CD3+ T cells ( 3 ). In the setting of clinical allo-HCT, frequency of donor graft-derived MAIT cells in the early post-HCT period has been linked with favorable transplant outcomes in a number of studies ( 58 , 59 ). We have recently reported a relationship between MAIT cells and transplant outcome, in a cohort of 118 PBSC graft recipients ( 59 ).…”

“…In the setting of clinical allo-HCT, frequency of donor graft-derived MAIT cells in the early post-HCT period has been linked with favorable transplant outcomes in a number of studies ( 58 , 59 ). We have recently reported a relationship between MAIT cells and transplant outcome, in a cohort of 118 PBSC graft recipients ( 59 ). A higher than median MAIT cell frequency at day 30 post-transplant was correlated with OS and decreased NRM.…”

“…A correlation between α-diversity and MAIT proportion and number in circulation at d+30 post-transplant has been observed ( 59 ). MAIT frequency has also been positively correlated with relative abundance of members of the classes Bacteroidia and Erysipelotrichia as well as the family Ruminococcaceae and genus Blautia ( 59 ). Blautia and Bifidobacterium spp.…”

“…The microbial analysis highlights that a diverse microbiome may be linked with good transplant outcomes because of its capacity to support protective cell populations, including MAIT cells. Surprisingly for an apparently regulatory population, single-cell RNA sequencing of purified MAIT cells from 5 allo-HCT patients revealed an upregulation of genes associated with effector function and cytotoxicity (granulysin, perforin 1, and C-C motif chemokine ligand 4 or GNLY, PRF1 , and CCL4 respectively) and migration (adhesion molecules integrin beta-2 and CD74) compared with healthy controls ( 59 ). Purified MAIT cells from HCT patients also demonstrated transcriptional downregulation of negative feedback inhibitors ( NFKBIA and TNFAIP3 or TNF alpha induced protein 3) of the NF-κB pathway ( 59 ).…”