期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：26
页码：8046-8051
DOI：10.1073/pnas.1508990112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAn attribute of adaptive immunity is the generation of memory cells that mount enhanced responses after rechallenge. While memory is best understood for {beta}T cell receptor-bearing lymphocytes, the properties of {gamma}{delta}T cells in the context of a secondary challenge have been less examined. After murine skin inflammation with imiquimod, IL-17-secreting {gamma}{delta}T cells expand in lymph nodes and traffic to skin where they persist as memory-like cells capable of rapid activation upon rechallenge. This enhanced secondary response is in part mediated by increased IL-1R1 expression. Expansion of potentially pathogenic memory cells in lymph nodes and redistribution throughout normal and inflamed skin may help explain the generalized worsening of psoriasis reported in patients undergoing localized skin treatment with imiquimod. Gamma delta ({gamma}{delta}) T cells represent a major IL-17 committed T-cell population ({gamma}{delta}T17 cells) in the mouse dermis. Following exposure to the inflammatory agent imiquimod (IMQ) the V{gamma}4+ subset of {gamma}{delta}T 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 {gamma}{delta}T17 cells sensitize distant sites to inflammation has been unknown. Here we show that expanded V{gamma}4+ {gamma}{delta}T17 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 V{gamma}4+ {gamma}{delta}T cells upon imiquimod challenge. Transfer experiments confirm that memory-like V{gamma}4+ {gamma}{delta}T17 cells respond more rapidly. Memory-like V{gamma}4+ {gamma}{delta}T17 cells are distinguished by greater IL-1R1 expression and more proliferation in response to IL-1{beta}. 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 {gamma}{delta}T-cell population.
