Human MAIT cells are devoid of alloreactive potential: prompting their use as universal cells for adoptive immune therapy

Abstract

BackgroundMucosal associated invariant T (MAIT) cells are semi-invariant T cells that recognize microbial antigens presented by the highly conserved MR1 molecule. MAIT cells are predominantly localized in the liver and barrier tissues and are potent effectors of anti - microbial defense. MAIT cells are very few at birth and accumulate gradually over a period of about 6 years during infancy. The cytotoxic potential of MAIT cells, as well as their newly described regulatory and tissue repair functions, open the possibility of exploiting their properties in adoptive therapy. A prerequisite for their use as “universal” cells would be a lack of alloreactive potential, which remains to be demonstrated.MethodsWe used ex vivo, in vitro and in vivo models to determine if human MAIT cells contribute to allogeneic responses.ResultsWe show that recovery of MAIT cells after allogeneic hematopoietic stem cell transplantation recapitulates their slow physiological expansion in early childhood, independent of recovery of conventional T cells. In vitro, signals provided by allogeneic cells and cytokines do not induce sustained MAIT cell proliferation. In vivo, human MAIT cells do not expand nor accumulate in tissues in a model of T-cell mediated xenogeneic graft-versus-host disease (GVHD) in immunodeficient mice.ConclusionsAltogether, these results provide evidence that MAIT cells are devoid of alloreactive potential and pave the way for harnessing their translational potential in universal adoptive therapy overcoming barriers of HLA disparity.

CAR products from novel sources: a new avenue for the breakthrough in cancer immunotherapy

“…Indeed, substantial infiltration of MAIT cells has been observed within the TME ( 54 – 56 ). Moreover, due to the non-polymorphic nature of MR1, MAIT cells are devoid of alloreactivity, similar to the behavior observed in NKT cells ( 57 ). Clinical data further supports this, showing an association between increased MAIT cells in grafts and reduced incidence of GVHD following HSCT ( 58 – 61 ).…”

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

“…This is attributed to their restriction by MR1 and their non-recognition of mismatched major histocompatibility complex (MHC) molecules and protein autoantigens ( 105 ). Rigorous assessments, including in vitro studies and xenogeneic GvHD mouse models, consistently affirm the GvHD-free safety profile of MAIT cells ( 108 ). Recent research endeavors have shed light on the multifaceted advantages of MAIT cells, extending beyond their GvHD-free safety profile.…”

MAIT Cells Modulate Innate Immune Cells and Inhibit Colon Cancer Growth

“…Specifically, due to their abundance at mucosal tissues, there has been an increasing interest in the role of MAIT cells in mucosal tissue-associated cancers. MAIT cells are a promising potential candidate for cancer immunotherapies: MAIT cells lack alloreactive potential, thus having an advantage over the use of conventional T cells with HLArestrictions for the application of universal, non-donor-restrictive adoptive cell therapy (24).…”

“…Reports have suggested both pro-and anti-tumor activity of MAIT cells, with some studies demonstrating a modulating effect on Natural Killer (NK) cell anti-tumor activity (21)(22)(23). In addition, due to their lack of alloreactive potential and cytotoxic capacity, MAIT cells have been considered for use in immunotherapy (24)(25)(26). Evidently, the role of MAIT cells in cancer is complex and context-dependent, warranting further studies in various types of cancer, particularly their potential to interact with other immune cell types.…”