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T H 17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of T H 17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-ß signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in T H 17 cells. Our data thus indicate a key function of T H 17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of T H 17 cells with regard to environmental changes.

Adaptive immunity provides life-long protection by generating central and effector memory T cells and the most recently described tissue resident memory T (T-RM) cells. However, the cellular origin of CD4 T-RM cells and their contribution to host defense remain elusive. Using IL-17A tracking-fate mouse models, we found that a significant fraction of lung CD4 T-RM cells derive from IL-17A-producing effector (T(H)17) cells following immunization with heat-killed Klebsiella pneumonia (Kp). These exT(H)17 T-RM cells are maintained in the lung by IL-7, produced by lymphatic endothelial cells. During a memory response, neither antibodies, gamma delta T cells, nor circulatory T cells are sufficient for the rapid host defense required to eliminate Kp. Conversely, using parabiosis and depletion studies, we demonstrated that exT(H)17 T-RM cells play an important role in bacterial clearance. Thus, we delineate the origin and function of airway CD4 T-RM cells during bacterial infection, offering novel strategies for targeted vaccine design.