An Unconventional View of T Cell Reconstitution After Allogeneic Hematopoietic Cell Transplantation

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is performed as curative-intent therapy for hematologic malignancies and non-malignant hematologic, immunological and metabolic disorders, however, its broader implementation is limited by high rates of transplantation-related complications and a 2-year mortality that approaches 50%. Robust reconstitution of a functioning innate and adaptive immune system is a critical contributor to good long-term patient outcomes, primarily to prevent and overcome post-transplantation infectious complications and ensure adequate graft-versus-leukemia effects. There is increasing evidence that unconventional T cells may have an important immunomodulatory role after allo-HCT, which may be at least partially dependent on the post-transplantation intestinal microbiome. Here we discuss the role of immune reconstitution in allo-HCT outcome, focusing on unconventional T cells, specifically mucosal-associated invariant T (MAIT) cells, γδ (gd) T cells, and invariant NK T (iNKT) cells. We provide an overview of the mechanistic preclinical and associative clinical studies that have been performed. We also discuss the emerging role of the intestinal microbiome with regard to hematopoietic function and overall immune reconstitution.

Keywords: allogeneic transplantation; immune reconstitution; invariant NK T (iNKT) cells; microbiome; mucosal invariant T cells (MAIT) cells; unconventional T cells; γδ T cells.

Figure 1

Timeline of immune reconstitution after allo-HCT. Myeloid reconstitution takes place in the early weeks post-transplantation, followed by the lymphoid compartment. NK cells typically return to steady state number first, followed by conventional T cells which reach pre-transplantation levels during the first 3 to 6 months. B cells commonly do not fully reconstitute until years after allo-HCT. The reconstitution of the unconventional compartment differs depending on the cell type and is a subject of ongoing investigation. The immune subsets measured in the periphery reflect cells from the donor graft that have been maintained and expanded (early) followed by true reconstitution of the hematopoietic compartment via the bone marrow progenitors transferred in the graft (which can occur quite early in the case of some myeloid lineages, but on a much longer time scale with respect to T cells that must undergo thymic education). While some post-transplantation reconstitutition mimicks immune system development in early life, there are many features unique to HCT.

Figure 2

The gut microbiome in immune reconstitution. The intestinal microbiota produces a variety of metabolites which are biologically active. Some of these products circulate systemically and there is emerging evidence regarding their immunomodulatory potential. Based on the current literature, we hypothesize that the circulating bacterial products may influence peripheral immune reconstitution after allo-HCT.