Inflammation induces dermal Vγ4+ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

F Ramírez-Valle, EE Gray… - Proceedings of the …, 2015 - National Acad Sciences
F Ramírez-Valle, EE Gray, JG Cyster
Proceedings of the National Academy of Sciences, 2015National Acad Sciences
Gamma delta (γδ) T cells represent a major IL-17 committed T-cell population (γδT17 cells)
in the mouse dermis. Following exposure to the inflammatory agent imiquimod (IMQ) the
Vγ4+ subset of γδT cells produce IL-17 in the skin and expand rapidly in draining lymph
nodes (LNs). Local IMQ treatment in humans is known to exacerbate psoriasis skin lesion
activity at distant sites. Whether expanded γδT17 cells sensitize distant sites to inflammation
has been unknown. Here we show that expanded Vγ4+ γδT17 cells egress from LNs in a …
Gamma delta (γδ) T cells represent a major IL-17 committed T-cell population (γδT17 cells) in the mouse dermis. Following exposure to the inflammatory agent imiquimod (IMQ) the Vγ4+ subset of γδT cells produce IL-17 in the skin and expand rapidly in draining lymph nodes (LNs). Local IMQ treatment in humans is known to exacerbate psoriasis skin lesion activity at distant sites. Whether expanded γδT17 cells sensitize distant sites to inflammation has been unknown. Here we show that expanded Vγ4+ γδT17 cells egress from LNs in a fingolimod (FTY720)-sensitive manner and use C-C chemokine receptor type 2 to accumulate in inflamed skin where they augment neutrophil recruitment and inflammation. They also travel to noninflamed skin and peripheral LNs and remain in elevated numbers at these distant sites for at least 3 mo. Sensitized mice show more rapid skin inflammation and greater proliferation and IL-17 production by Vγ4+ γδT cells upon imiquimod challenge. Transfer experiments confirm that memory-like Vγ4+ γδT17 cells respond more rapidly. Memory-like Vγ4+ γδT17 cells are distinguished by greater IL-1R1 expression and more proliferation in response to IL-1β. These findings establish that local skin inflammation leads to faster and stronger secondary responses to the same stimulus through long-term and systemic changes in the composition and properties of the dermal γδT-cell population.
National Acad Sciences