Human T cells modulate myeloid-derived suppressor cells through a TNF-α-mediated mechanism

Myeloid-derived suppressor cells (MDSC) represent an innate immune cell subset capable of suppressing T-cell responses in cancer and chronic inflammation. While the effect of MDSC on T cells has been defined thoroughly, the reciprocal impact of T cells on MDSC homeostasis remains poorly understood. Therefore, we comprehensively analyzed the effect of different T-cell subsets on the generation and survival of human MDSC. Using an in vitro MDSC generation assay, we demonstrate that unstimulated CD4(+), but not CD8(+) T cells, induce polymorphonuclear MDSC (PMN-MDSC) from CD33(+) myeloid cells. This effect was dependent on direct cell-cell contact and required TNF-alpha signaling. Soluble TNF-alpha was dispensable for PMN-MDSC generation, suggesting that transmembrane TNF-alpha is involved in that trans-cellular process. Stimulated human CD3(+) T cells delayed the apoptosis of PMN-MDSC, which was independent of TNF-alpha signaling or direct cell-cell contact, but was recapitulated by IL-2. Taken together, our study shows that human T cells modulate MDSC generation and survival through two distinct mechanisms and thereby fine-tune the homeostasis of human MDSC in a regulated manner.