Immunoregulatory functions of mTOR inhibition

Abstract

The atypical serine/threonine protein kinase mammalian target of rapamycin (mTOR) has an important role in the modulation of both innate and adaptive immune responses. A complex formed between the immunosuppressive drug rapamycin and the immunophilin FK506-binding protein 1A, 12 kDA (FKBP12) inhibits mTOR kinase activity. mTOR functions in at least two multi-protein complexes: mTOR complex 1 (mTORC1) and mTORC2. mTOR in mTORC1 is highly sensitive to inhibition by rapamycin, whereas mTOR in mTORC2 is resistant to rapamycin. mTORC1 regulates cell growth downstream of phosphoinositide 3-kinase–AKT signalling, in which active mTORC1 phosphorylates S6 kinase (S6K1) and the eukaryotic translation initiation factor-binding protein 1 (EIF4EBP1). Both of these activities promote mRNA translation and cell growth. Rapamycin exerts many effects on the differentiation and function of professional antigen-presenting cells (APCs). mTOR inhibition by rapamycin impedes antigen uptake and can modulate antigen presentation by dendritic cells (DCs); its differential effects on cytokine production and chemokine receptor expression by DCs regulate interactions between innate and adaptive immune cells. Recent findings have shed light on previously unappreciated effects of mTOR inhibition on T cells. Rapamycin induces thymic involution, whereas the ontogeny of naturally occurring regulatory T (T_Reg) cells seems to be less affected. During conventional T cell activation, rapamycin-mediated mTOR inhibition blocks cell cycle progression and can sequester activated T cells in secondary lymphoid tissues. By contrast, rapamycin causes an increase in the frequency of FOXP3 (forkhead box P3)⁺ T cells, reflecting both the ability of T_Reg cells to proliferate in the presence of rapamycin and the promotion of FOXP3 expression in peripheral T cells that are then converted into modulators of immune reactivity. mTOR inhibition is a promising therapeutic strategy to prevent rejection in transplantation and for autoimmune disease. Differential effects of rapamycin on T cells and T_Reg cells (both naturally occurring and inducible) favour its ability to promote tolerance in tolerance-enhancing protocols. In addition, adoptively transferred rapamycin-conditioned APCs inhibit organ allograft rejection and graft-versus-host disease following haematopoietic cell transplantation. Ongoing and future areas of enquiry, which could prove fruitful, include distinguishing the role of mTORC1 and mTORC2 in the regulation of immune responses and tolerance, investigating the role of the mTOR–survivin–aurora B complex in T cell activation and ascertaining the mechanisms that determine T_Reg cell resistance to rapamycin and mTOR-mediated regulation of FOXP3 expression, as well as their relevance to therapy.