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

BACKGROUND: Mucosal-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 antimicrobial defense. MAIT cells are very few at birth and accumulate gradually over a period of about 6 years during the 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. METHODS: We used ex vivo, in vitro and in vivo models to determine if human MAIT cells contribute to allogeneic responses. RESULTS: We show that recovery of MAIT cells after allogeneic hematopoietic stem cell transplantation recapitulates their slow physiological expansion in early childhood, independent of recovery of non-MAIT 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 in immunodeficient mice. CONCLUSIONS: Altogether, 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. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT02403089.

Mucosal-Associated Invariant T Cell Levels Are Reduced in the Peripheral Blood and Lungs of Children With Active Pulmonary Tuberculosis.

Mucosal associated invariant T (MAIT) cells are unconventional, semi-invariant T lymphocytes that recognize microbial-derived vitamin B2 (riboflavin) biosynthesis precursor derivatives presented by the monomorphic MHC class 1-related (MR1) molecule. Upon microbial infection, MAIT cells rapidly produce cytokines and cytotoxic effectors, and are thus important players in anti-microbial defense. MAIT cells are protective in experimental models of infection and are decreased in the blood of adult patients with bacterial infections, including Mycobacterium tuberculosis (Mtb). In children, the risk of rapid progression to active tuberculosis (TB) following Mtb infection is higher than in adults. Whether MAIT cells influence the outcome of Mtb infection in children is therefore, an important issue. We analyzed MAIT cell numbers and phenotype in 115 children investigated for pulmonary TB and determined their potential correlation with disease progression. MAIT cells were reduced in numbers and activated in the peripheral blood of children with active TB as compared to those with latent TB infection (LTBI) and healthy children. Moreover, MAIT cells did not accumulate and did not proliferate in the lung of children with active TB. These results suggest that MAIT cells may be important in preventing progression of Mtb infection to active TB in children.

Ontogeny of human mucosal-associated invariant T cells and related T cell subsets.

Mucosal-associated invariant T (MAIT) cells are semi-invariant Vα7.2+ CD161highCD4- T cells that recognize microbial riboflavin precursor derivatives such as 5-OP-RU presented by MR1. Human MAIT cells are abundant in adult blood, but there are very few in cord blood. We longitudinally studied Vα7.2+ CD161high T cell and related subset levels in infancy and after cord blood transplantation. We show that Vα7.2+ and Vα7.2- CD161high T cells are generated early during gestation and likely share a common prenatal developmental program. Among cord blood Vα7.2+ CD161high T cells, the minority recognizing MR1:5-OP-RU display a TRAV/TRBV repertoire very similar to adult MAIT cells. Within a few weeks of life, only the MR1:5-OP-RU reactive Vα7.2+ CD161high T cells acquire a memory phenotype. Only these cells expand to form the adult MAIT pool, diluting out other Vα7.2+ CD161high and Vα7.2- CD161high populations, in a process requiring at least 6 years to reach adult levels. Thus, the high clonal size of adult MAIT cells is antigen-driven and likely due to the fine specificity of the TCRαß chains recognizing MR1-restricted microbial antigens.

Anti-adenovirus humoral responses influence on the efficacy of vaccines based on epitope display on adenovirus capsid.

The efficacy of recombinant adenoviruses (Ads) vaccine vectors is diminished by the high prevalence of anti-Ad antibodies (Abs) that hampers gene transfer. Epitope display on Ad capsid constitutes an alternative approach to bypass anti-Ad Ab capacity from blocking antigen expression. To understand the role of the epitope insertion site, an ovalbumin-derived epitope was genetically inserted into either Ad hexon or fiber proteins. Hexon-modified Ads triggered higher anti-ovalbumin Ab responses after one injection but surprisingly fiber-modified Ads were by far more potent after two or several administrations. Our data unravel a role for anti-Ad humoral immunity in controlling anti-epitope humoral responses.