Balanced T cell subsets for good health

On page 1381, Lochner et al. expose the promiscuity of a transcription factor that was previously thought to be exclusive to inflammatory T helper (Th) 17 cells. They now find that this protein is also expressed by a group of regulatory T (T reg) cells that keeps Th17 cells in line.

Both cell types stem from naive CD4⁺ T cells, depending on the cytokines in attendance: T reg cells are induced by high levels of TGF-β, whereas inflammatory Th17 cells are induced by lower levels of TGF-β and IL-6. Each subset foils the other by secreting cytokines with opposite functions. When T reg cells are missing, mice have more Th17 cells and develop inflammatory diseases, suggesting that one subset might limit the other to maintain health.

Th17 cells were previously detected based on their expression of the transcription factor RORγt, which is required for their development. But Lochner et al. now find that in healthy mice, the RORγt⁺ T cell population includes a group of cells that does not produce the signature Th17 cytokine IL-17 when activated. These cells instead secreted the suppressive cytokine IL-10 and expressed the T reg cell–specific transcription factor Foxp3 alongside RORγt.

These RORγt-expressing T reg cells expressed ligands for chemokine receptors found on Th17 cells. Mice that lacked these receptors had more Th17 cells, suggesting that the T reg cells might lure the inflammatory cells into a suppressive environment.

The T reg cells also controlled their nemeses in a more direct way. In RORγt⁺ T reg cells, RORγt was bound by Foxp3, suggesting that Foxp3 may actively derail Th17 development. Consistent with this idea, naive CD4⁺ T cells cultured with TGF-β alone first expressed RORγt and later expressed Foxp3, which drove them to become T reg cells. The delayed induction of Foxp3 could be prevented by IL-6, thus freeing RORγt to drive Th17 differentiation. Whether suppressive cytokines can reverse this switch is yet to be determined.

Both RORγt-expressing populations were present in equal numbers in most tissues of healthy mice, suggesting mutual control between the two cell types. Both populations expanded proportionally in response to inflammation or infection, which is probably important to ensure a damage-free recovery.