Cell-based immunosuppressive therapies hold great promise for preventing transplant rejection and are the subject of active research. Now, Riquelme et al. provide further insight into the role of regulatory macrophages (Mregs) in controlling the immune response of kidney transplant recipients.
“Previous work demonstrated that allograft-infiltrating, monocyte-derived macrophages with immune regulatory functions are indispensable for establishing and maintaining transplantation tolerance in animal models,” explains lead investigator James Hutchinson. The researchers generated Mregs in vitro from CD14+ blood monocytes to study their interactions with allogeneic T cells. Co-culture of FOXP3– CD4+ T cells and Mregs demonstrated that Mregs induced the formation of IL-10-producing FOXP3+ regulatory T (Treg) cells, so-called Mreg-induced Treg cells (miTreg cells); this effect required a direct interaction between the two cell types. Furthermore, using inhibitors, the researchers established that the Mreg-induced formation of miTreg cells involves multiple non-redundant signalling pathways, including those mediated by indoleamine 2,3-dioxygenase (IDO), transforming growth factor-β (TGFβ), retinoic acid, Notch and progestagen-associated endometrial protein (PAEP; also known as glycodelin).
Transcriptional profiling of miTreg cells revealed that these cells expressed higher levels of T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT; a negative regulator of T cell-mediated immunity) than non-induced Treg cells. Importantly, adoptive transfer of allogeneic Mregs to patients prior to living donor kidney transplantation led to an enrichment of Treg cells phenotypically similar to miTreg cells.
“Mregs seem to elicit a TIGIT+ Treg cell response after adoptive transfer, which might sustain transplant-protective regulation beyond the lifespan of transferred Mregs,” says Hutchinson.
Riquelme, P. et al. TIGIT+ iTregs elicited by human regulatory macrophages control T cell immunity. Nat. Commun. 9, 2858 (2018)
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Otto, G. Mregs kick-start transplant tolerance. Nat Rev Nephrol 14, 599 (2018). https://doi.org/10.1038/s41581-018-0049-8