CCL25 induces α₄β₇ integrin‐dependent migration of IL‐17⁺γδ T lymphocytes during an allergic reaction

Abstract

Herein, we provide evidence that during allergic inflammation, CCL25 induces the selective migration of IL-17 + γδ T cells mediated by α 4 β 7 integrin. Intrapleural injection of CCL25 into ovalbumin (OVA)-immunized C57BL/6 mice triggered the accumulation of γδ T lymphocytes expressing CCR9 (CCL25 receptor) and α 4 β 7 integrin in the pleura, but failed to attract αβ T lymphocytes. CCL25 attracted CCR6 + γδ T cells producing IL-17 (but not IFN-γ or IL-4). OVA challenge triggered increased production of CCL25 followed by the accumulation of CCR9 + , α 4 β 7 + , and CCR6 + /IL-17 + γδ T cells into the pleural cavities of OVA-immunized mice, which was inhibited by the in vivo neutralization of CCL25. The in vivo blockade of α 4 β 7 integrin also inhibited the migration of IL-17 + γδ T lymphocytes (but not of αβ T lymphocytes) into mouse pleura after OVA challenge, suggesting that the CCL25/α 4 β 7 integrin pathway is selective for γδ T cells. In addition, α 4 β 7 integrin blockade impaired the in vitro transmigration of γδ T cells across endothelium (which expresses α 4 β 7 ligands VCAM-1 and MadCAM-1), which was induced by CCL25 and by cell-free pleural washes recovered from OVA-challenged mice. Our results reveal that during an allergic reaction, CCL25 drives IL-17 + γδ T-cell mobilization to inflamed tissue via α 4 β 7 integrin and modulates IL-17 levels. Keywords: Adhesion molecules IntroductionLymphocytes bearing the γδ T-cell receptor (TCR) comprise a minor T-lymphocyte subset in blood and secondary lymphoid tissues and are preferentially localized in epithelial and mucosal tissues [1,2]. This unique subset of lymphocytes can provide rapid tissue-specific immune responses, without the requirement of antiCorrespondence: Dr. Carmen Penido e-mail: cpenido@far.fiocruz.br gen presentation or clonal expansion, and is able to produce a large repertory of Th1-, Th2-, and Th17-associated cytokines [2][3][4][5][6]. These characteristics make γδ T cells a crucial first line of defense during infection, tissue damage, or stress.γδ T cells have been shown to migrate into the airways during allergic inflammation highly controlled by a chemotactic gradient of chemokines produced in tissue [5,[7][8][9][10][11]. We have previously demonstrated that allergen-induced γδ T-cell accumulation is * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1250-1260 Immunomodulation 1251 paralleled with a marked production of chemokines in the tissue, including CCL25/TECK [11]. CCL25 is mostly described as a homeostatic chemokine that plays a major role in T-cell development in the thymus and in intraepithelial lymphocytes (IELs) homing into small intestine mucosa [12]. Recent data have provided evidence that CCL25 production increases during inflammatory processes that take place at nonmucosal tissues, such as autoimmune arthritis, atherosclerosis, and allergy [11,13,14]. Moreover, we and others have shown that γδ T lymphocytes migrate in vitro toward CCL25, via its counterpart receptor CCR9 [11,...

Driving IL‐17+ γδ T‐cell migration in allergic reactions: A new “inflammatory” role for the “homeostatic” chemokine CCL25

“…Importantly, this effect was specific to the γδ17 subset, since both αβ T cells and the remaining IL-17 − γδ T cells were still recruited despite CCL25 neutralization. Consistent with this, the exogenous provision of CCL25 attracted γδ17 cells but not IFN-γ + or IL-4 + γδ T cells, and this was associated with a selective increase in IL-17 levels in the mouse pleura [5]. In this commentary, I discuss three topics that contextualize the new findings by Costa et al [5]: first, the homeostatic versus inflammatory functions of CCL25; second, the migration of γδ T cells to sites of inflammation; and, third, the potential roles of IL-17 (and γδ17 cells) in allergic reactions.…”

“…Interestingly, although the β-chemokines CCL3 and CCL5 were also induced in allergic pleurisy (and can mediate γδ T-cell chemotaxis in vitro), neutralization experiments showed they were not essential for γδ T-cell recruitment. Thus, only CCL2/CCR2 played a nonredundant role in γδ T-cell migration to the inflammatory site in vivo [4].An important difference between these previous studies on CCL2/CCR2 [3,4] and the current one on CCL25/CCR9 [5] is that, while the former showed an impact on total γδ T-cell numbers, the latter only affects specifically the γδ17 subset. Thus, whereas CCR2 seems to be a determinant for γδ T-cell migration as a whole, CCR9 may be selective for γδ17 cells.…”

Protective Role of the Inflammatory CCR2/CCL2 Chemokine Pathway through Recruitment of Type 1 Cytotoxic γδ T Lymphocytes to Tumor Beds

“…2), typically associated with lymph node homing. Furthermore, CCL25 and CCL27, previously shown to control gd T cell migration under homeostatic or inflammatory conditions (24,33), were also equally expressed in WT and TCRd-deficient mice (Supplemental Fig. 2).…”

“…2). Recently, members of our team have shown that CCL25 and its receptor CCR9 control the migration and lung recruitment of a subset of gd T cells committed to IL-17 production in a model of allergic pleurisy (33). In fact, the effect of CCL25 was selective to IL-17 + gd cells-namely, not extending to IFN-g-producing gd T cells.…”

“…Namely, skin homing is controlled by CCL27 (27), whereas gut homing is directed by CCL25 (30). In contrast, CCL2 (31,32), CCL25 (33), and CXCL10 (34) have been shown to control murine gd T cell migration upon allergic (31,33) or microbial challenge (32,34). Strikingly, it is yet unknown which chemokine(s) among this large family of cytokines mediate gd T cell recruitment to tumor beds.…”