Abstract
The cytokine micro-environment can direct murine CD4+ T cells towards various differentiation lineages such as Th1, Th2 and Tregs even in the presence of rapamycin, which results in T cells that mediate increased in vivo effects. Recently, a new lineage of T cells known as Th9 cells that secrete increased IL-9 have been described. However, it is not known whether Th9 differentiation occurs in the presence of rapamycin or whether adoptively transferred donor Th9 cells would augment or restrict alloreactivity after experimental bone marrow transplantation. We found that CD4+ T cells that were co-stimulated and polarized with TGF-β and IL-4 in the presence or absence of rapamycin each yielded effector cells of Th9 phenotype that secreted increased IL-9 and expressed a transcription factor profile characteristic of both Th9 and Th2 cells (high GATA-3/low T-bet). Augmentation of T cell replete allografts with manufactured rapamycin resistant Th9 cells markedly reduced both CD4+ and CD8+ T cell engraftment and strongly inhibited allo-specific T cell secretion of IFN-γ. The potency of Th9 cell inhibition of alloreactivity was similar to that of rapamycin resistant Th2 cells. Importantly, rapamycin resistant Th9 cells persisted and maintained their cytokine phenotype, thereby indicating limited differentiation plasticity of the Th9 subset. As such, Th9 differentiation proceeds in the presence of rapamycin to generate a cell therapy product that maintains high IL-9 expression in vivo while inhibiting IFN-γ driven alloreactivity.
Highlights
CD4+ T helper subsets can differentiate into various lineages in response to environmental cues such as cytokines or ligand interactions
While IL-9 producing CD4+ T cells were previously classified as Th2 cells [2], recent studies have shown that Th9 cells are a distinct lineage of T helper cells [1,3]
The data presented here shows that Th9 cells: (1) can be polarized in the presence of rapamycin, (2) possess cytokine phenotype stability in vivo during allogeneic BMT; and (3) inhibit IFN-c mediated graft-versus-host-reactivity
Summary
CD4+ T helper subsets can differentiate into various lineages in response to environmental cues such as cytokines or ligand interactions. Of the various lineages of T helper subsets, Th9 cells are a recent addition. While IL-9 producing CD4+ T cells were previously classified as Th2 cells [2], recent studies have shown that Th9 cells are a distinct lineage of T helper cells [1,3]. Th9 cells can share mechanistic features of Th1 cells, as they have been associated with solid organ graft rejection [8], experimental peripheral neuritis [3] and anti-tumor responses [9]. There are somewhat conflicting data with respect to the role of Th9 cells in immunity, and no data exists concerning their potential role after experimental allogeneic bone marrow transplantation
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