Characterization of Human T Cells That Regulate Neutrophilic Skin Inflammation

Abstract

It is unknown whether neutrophilic inflammations can be regulated by T cells. This question was analyzed by studying acute generalized exanthematous pustulosis (AGEP), which is a severe drug hypersensitivity resulting in intraepidermal or subcorneal sterile pustules. Recently, we found that drug-specific blood and skin T cells from AGEP patients secrete high levels of the potent neutrophil-attracting chemokine IL-8/CXCL8. In this study, we characterize the phenotype and function of CXCL8-producing T cells. Supernatants from CXCL8+ T cells were strongly chemotactic for neutrophils, CXCR1, and CXCR2 transfectants, but not for transfectants expressing CXCR4, CX3CR1, human chemokine receptor, and RDC1. Neutralization experiments indicated that chemotaxis was mainly mediated by CXCL8, but not by granulocyte chemotactic protein-2/CXCL6, epithelial cell-derived neutrophil attractant-78/CXCL5, or growth-related oncogene-α,β,γ/CXCL1,2,3. Interestingly, ∼2.5% of CD4+ T cells in normal peripheral blood also produced CXCL8. In addition to CXCL8, AGEP T cells produced large amounts of the monocyte/neutrophil-activating cytokine GM-CSF, and the majority released IFN-γ and the proinflammatory cytokine TNF-α. Furthermore, apoptosis in neutrophils treated with conditioned medium from CXCL8+ T cells could be reduced by 40%. In lesional skin, CXCL8+ T cells consistently expressed the chemokine receptor CCR6, suggesting a prominent role for CCR6 in early inflammatory T cell recruitment. Finally, our data suggest that CXCL8-producing T cells facilitate skin inflammation by orchestrating neutrophilic infiltration and ensuring neutrophil survival, which leads to sterile pustular eruptions found in AGEP patients. This mechanism may be relevant for other T cell-mediated diseases with a neutrophilic inflammation such as Behçet’s disease and pustular psoriasis.

Human T Cells That Are Able to Produce IL-17 Express the Chemokine Receptor CCR6

“…Because IL-17-driven inflammation is characterized by neutrophil infiltration, it is of interest that CCR6 ϩ T cells in skin have been reported to produce CXCL8 (44) and that neutrophils have been reported both to produce CCL20 (47) and to express CCR6 following exposure to TNF-␣ (48). Moreover, IL-17 has been reported to be a potent inducer of CCL20 (45).…”

“…In mouse models of immune response and disease, CCR6 and/or CCL20 have been reported to have roles in Ab production and pathogeninduced T cell activation in the gut (25)(26)(27); delayed-type and contact hypersensitivity in the skin (28,29); allergic inflammation in the lung (30); inflammatory bowel disease (31,32); and graft-vs-host disease (33), models which depend on B cell and/or T cell and/or dendritic cell trafficking at epithelial sites. In humans, CCR6 can function to mediate arrest of T cells on dermal endothelial cells (41) and is highly expressed on T cells resident in both normal (42) and psoriatic (43,44) skin, and CCR6 and/or CCL20 have been implicated in the pathogenesis of rheumatoid arthritis (45) and inflammatory bowel disease (46). Psoriasis, rheumatoid arthritis, and inflammatory bowel disease are all autoimmune disorders in which Th17 cells are thought to play a critical part (13), and our data suggest that CCL20 and CCR6 may have a role in these disorders by recruiting Th17 cells to target tissues.…”

Short-Term Heat Exposure Inhibits Inflammation by Abrogating Recruitment of and Nuclear Factor-κB Activation in Neutrophils Exposed to Chemotactic Cytokines

“…4,35 T cells also release IL-8 and GM-CSF with subsequent neutrophil-mediated inflammation. 36 Furthermore, activated keratinocytes are a common source of GM-CSF in patients with atopic dermatitis. 37 Based on our in vivo observation that chemokine-induced neutrophil-specific skin inflammation was inhibited in mice exposed to heat, we focused on two aspects namely neutrophil recruitment, and activation of the proinflammatory NF-〉.…”

Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

“…In addition to the heterogeneity in circulating neutrophils evoked in earlier studies, specific inflammatory conditions can also favor the emergence of neutrophil subpopulations with distinct phenotypes. After a 72-h incubation of normal human blood neutrophils with a combination of GM-CSF, TNF-a and IL-4, mediators known to be present in inflammatory conditions such as early arthritis, allergic asthma and skin pustulosis, and to influence neutrophil survival and functions, 7,8,[20][21][22][23] we isolated and characterized a subset of neutrophils with a functional profile that is markedly different from that of freshly isolated neutrophils. Constituting 8-17% of the global neutrophil populations exposed to the cytokines, these cells have substantially increased lifespan persisting beyond 72 h. They have a unique inflammatory profile seen in the pattern of surface marker expression, production of superoxide anions (O 2 À ), phagocytosis, leukotriene biosynthesis, chemotactic responses and degranulation.…”