Mucosal-Associated Invariant T Cells in Regenerative Medicine

Abstract

Although antibiotics to inhibit bacterial growth and small compounds to interfere with the productive life cycle of human immunodeficiency virus (HIV) have successfully been used to control HIV infection, the recent emergence of the drug-resistant bacteria and viruses poses a serious concern for worldwide public health. Despite intensive scrutiny in developing novel antibiotics and drugs to overcome these problems, there is a dilemma such that once novel antibiotics are launched in markets, sooner or later antibiotic-resistant strains emerge. Thus, it is imperative to develop novel methods to avoid this vicious circle. Here, we discuss the possibility of using induced pluripotent stem cell (iPSC)-derived, innate-like T cells to control infection and potential application of these cells for cancer treatment. Mucosal-associated invariant T (MAIT) cells belong to an emerging family of innate-like T cells that link innate immunity to adaptive immunity. MAIT cells exert effector functions without priming and clonal expansion like innate immune cells and relay the immune response to adaptive immune cells through production of relevant cytokines. With these characteristics, MAIT cells are implicated in a wide range of human diseases such as autoimmune, infectious, and metabolic diseases, and cancer. Circulating MAIT cells are often depleted by these diseases and often remain depleted even after appropriate remedy because MAIT cells are susceptible to activation-induced cell death and poor at proliferation in vivo, which threatens the integrity of the immune system. Because MAIT cells have a pivotal role in human immunity, supplementation of MAIT cells into immunocompromised patients suffering from severe depletion of these cells may help recapitulate or recover immunocompetence. The generation of MAIT cells from human iPSCs has made it possible to procure MAIT cells lost from disease. Such technology creates new avenues for cell therapy and regenerative medicine for difficult-to-cure infectious diseases and cancer and contributes to improvement of our welfare.

Keywords: cancer; cell therapy; drug resistance; human immunodeficiency virus; induced pluripotent stem cells; infectious diseases; mucosal-associated invariant T cells; regenerative medicine.

Figure 1

Cell surface antigens, effector molecules, cytokines, and effector functions of MAIT and reMAIT cells. reMAIT cell differentiation from MAIT cell-derived iPS cells (MAIT-iPS cells) via cell reprogramming of MAIT cells is illustrated (upper panel). Representative antigens and effector molecules present in MAIT cells (left panel) and in reMAIT cells (right panel) are shown. The transcription factors rich in MAIT cells, such as promyelocytic leukemia zinc finger (PLZF) and related orphan receptor C (RORC), are also depicted, but the presence of PLZF in reMAIT cells has not been determined. Effector molecules and cytokines from MAIT and reMAIT cells are shown. In addition, the target cells for the cytolytic activity and antimycobacterial activity of MAIT cells and reMAIT cells are indicated. “?” indicates not determined.

Figure 2

Adoptive transfer of reMAIT cells for cell therapy. Fully matured reMAIT cells could be prepared before adoptive transfer (upper panel) or directly transferred into the patient (middle panel). In vitro-cultured reMAIT cells could further be maturated and expanded through interaction with double-positive (DP) T cells followed by incubation with B cells in vitro before adoptive transfer (upper panel). Alternatively, reMAIT cells could directly be transferred into patients for autonomous maturation and expansion in vivo (middle panel). Potential targets for cell therapy with reMAIT cells are indicated (lower panel).

Figure 3

A novel mouse model for studying the role of MAIT cells in health and disease. The strategy to generate mice rich in MAIT cells is summarized. Mouse (m) MAIT cells are enriched from laboratory mice (e.g., C57BL/6) by combination of cell surface antigens. mMAIT-enriched fractions are subjected to cell reprogramming to generate iPS cells. Induced pluripotent stem cells from mMAIT cells (referred as mMAIT-iPS cells) are differentiated into mouse MAIT cells (referred as m-reMAIT cells) via a standard T cell lineage differentiation protocol. Maturation and expansion of m-reMAIT cells are assessed in congenic mice upon adoptive transfer. Once m-reMAIT cells settle in congenic mice, mice could be used to model various diseases, such as infectious, autoimmune, and metabolic diseases, and cancer, to decipher the role of mMAIT cells.