After bone marrow cell transplant between imperfectly matched donors and patients, there are many secondary complications that can arise, including increased risk of infection and graft-versus-host disease (GVHD). Due to the nature of cell transplantation and the need for immune reconstitution, subsets of immune cells should be followed post-transplant to better understand their roles in the reestablishment of a functional immune system. To date, the effects of mucosal-associated invariant T (MAIT) cells on immune reconstitution and subsequent outcomes are unknown. MAIT cells are a subset of T cells that are characterized as displaying innate effector-like qualities, such as defending against microbial infection. After activation by antigen presentation, MAIT cells can lyse infected cells as well as secrete pro-inflammatory cytokines. In order to study the immune reconstitution of MAIT cells, researchers from the Turtle (Clinical Research Division) and Fredricks (Clinical Research / Vaccine and Infectious Diseases Divisions) laboratories followed over 100 peripheral blood stem cell transplant (PBSCT) recipients in a longitudinal MAIT cell study.
The kinetics of MAIT cell reconstitution were followed in PBSCT recipients after myeloablative therapy, which kills immune cells in the bone marrow, or nonmyelablative conditions. The results showed no difference between groups. In both cases, after preconditioning therapy, MAIT cells were nearly eliminated at the time of donor infusion and rapidly rebounded to a plateau at day 30, remaining lower than healthy controls 1 year after transplant. Looking more closely at the MAIT cells, the group found that the population making up the rapid recovery was primarily transferred MIAT cells from the donor. Next, the group followed MAIT cell reconstitution in recipients of umbilical cord blood (UCB) grafts. These grafts contain lower numbers of MAIT cells than PBSC grafts. As expected based on their first finding, the UCB graft patients had a reduced MAIT cell population after transplant, providing further evidence that transferred cells are proliferating to make up the new post-transplant population.
In order to explain donor MAIT cell proliferation after HCT, cell activation and proliferation was studied in vitro. Proliferation was induced by both T cell receptor (TCR) stimulation and inflammatory cytokine signals; neither signal alone was enough to stimulate the cells. This result suggests that the post-transplant environment is conducive to induction of these signals. Since HCT patients have a compromised gastrointestinal (GI) mucosal barrier, altered microbiota and inflammation due to transplant, the group hypothesized that these changes provide the needed signals for cell proliferation. To test if different GI microbiota might contribute to differential proliferation, specific bacterial species were quantified. This led to the discovery that Blautia species spp. and Bifidobacterium longum were associated with higher MAIT cell counts.
Taken together, these data suggest that both bacteria-induced TCR signaling and inflammatory cytokines induced by transplantation are the reason for the rapid increase in MAIT cells and that the failure of this population to fully recover could be the clearing of transplantation-induced inflammation over time. To analyze if there was an association of GVHD with MAIT cell counts, a Cox regression model was used. Results indicated that low MAIT cell counts in blood may be associated with diagnosis of GVHD. When asked about the work, Dr. Turtle said, “The work describes how MAIT cells (a bacteria-responsive T cell subset) recover after transplant and shows that in large part, the recovery is derived from direct transfer of MAIT cells in the graft, likely augmented by the presence of inflammation after transplant and MAIT cell TCR ligands provided by the GI microbiota. We show that certain types of transplant (cord, haplo with post-HCT Cy) have poor MAIT cell recovery. Overall, the study suggests that the composition of the gastrointestinal microbiota could influence immune cell recovery and potentially complications after allogeneic transplantation; however, additional studies are needed.”
Funding was provided by National Institutes of Health.
Bhattacharyya A, Hanafi L-A, Sheih A, Golob JL, Srinivasan S, Boeckh MJ, Pergam SA, Mahmood S, Baker KK, Gooley TA, Milano F, Fredricks DN, Riddell SR, Turtle CJ. (2017). Graft-Derived Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant.