Expansion of Functional Human Mucosal-Associated Invariant T Cells via Reprogramming to Pluripotency and Redifferentiation

Abstract

Mucosal-associated invariant T (MAIT) cells play an important physiological role in host pathogen defense and may also be involved in inflammatory disorders and multiple sclerosis. The rarity and inefficient expansion of these cells have hampered detailed analysis and application. Here, we report an induced pluripotent stem cell (iPSC)-based reprogramming approach for the expansion of functional MAIT cells. We found that human MAIT cells can be reprogrammed into iPSCs using a Sendai virus harboring standard reprogramming factors. Under T cell-permissive conditions, these iPSCs efficiently redifferentiate into MAIT-like lymphocytes expressing the T cell receptor Vα7.2, CD161, and interleukin-18 receptor chain α. Upon incubation with bacteria-fed monocytes, the derived MAIT cells show enhanced production of a broad range of cytokines. Following adoptive transfer into immunocompromised mice, these cells migrate to the bone marrow, liver, spleen, and intestine and protect against Mycobacterium abscessus. Our findings pave the way for further functional analysis of MAIT cells and determination of their therapeutic potential.

Regeneration of CD8αβ T Cells from T-cell–Derived iPSC Imparts Potent Tumor Antigen-Specific Cytotoxicity

“…In keeping with this idea, we have recently succeeded in regenerating MART1-specific CTLs from iPSCs originally derived from CTLs of a melanoma patient (14). Other groups also have regenerated viral antigen-specific T cells (15,16), T cells expressing an invariant TCRs (17)(18)(19), and T cells that were genetically engineered to express a so-called chimeric antigen receptor (CAR; ref. 20).…”

Mucosal-associated invariant T cells from induced pluripotent stem cells: A novel approach for modeling human diseases

“…High expression levels of CD161 in MAIT cells are accompanied by RORγt, IL-23R and IL-21R, markers associated with Th17/Tc17 type T cells [11,19,20] . Furthermore, MAIT cells possess PLZF, indicating the capacity to promptly produce cytokines upon stimulation without priming [7,17] and CD26 + , a serine exodipeptidase, which processes chemokines in the extracellular matrix [20,21] . Accordingly, MAIT cells have the potential to release a variety of cytokines under various conditions: Interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-2, IL-4, IL-10, IL-17, IL-22, granzymes, and others, which anticipates the multifaceted roles in health and diseases [11,12,22] .…”

“…ESCs prepared through nuclear transfer with hepatic NKT cells (ntESCs), harboring in-frame rearranged TCRα (Vα14-Jα18), gave raise to T lymphocytes exclusively comprising NKT cells (> 94%) when ntESCs were subjected to the OP9/OP9-DL system, which is well-known to promote T cell lineage differentiation from pluripotent stem cells [64,65,72,73] . We have exploited a corollary that iPSCs derived from MAIT cells would efficiently redifferentiate into MAIT cells under the same conditions, because MAIT cells are innatelike T cells, and these iPSCs possess a rearranged TCRα (Vα7.2-Jα33), specific for MAIT cells [21] . This turned out to be the case.…”

“…SeV is superior to other viruses, such as lentivirus, in that SeV does not integrate into the host genome, thus leaving the genomic DNA free from interruptions [21,67,69,74] . As expected, MAIT-iPSCs successfully redifferentiated into MAIT cell-like cells expressing Vα7.2, CD3, CD161, and IL-18Rα (reMAIT cells) with high efficiency (> 98%) in T-cell-permissive conditions (Figure 2) [21] .…”

Harnessing the antibacterial and immunological properties of mucosal-associated invariant T cells in the development of novel oral vaccines against enteric infections

“…However, the range of cytokines produced by activated MAIT cells is narrower than activated iNKT cells [43]. Cytokine secretion from human CB MAIT cells has been characterized in supernatants following in vitro stimulation with E. coli fed monocytes, CD3/CD28 and PMA/Ionomycin [71]. Complete cytokine and chemokine profiling in these cells demonstrated strong responses to E. coli fed monocytes but a limited response to anti-CD3/CD28 or PMA/Ionomycin.…”