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Th2 Differentiation in Distinct Lymph Nodes Influences the Site of Mucosal Th2 Immune-Inflammatory Responses¹

Department of Pathology and Molecular Medicine, Division of Respiratory Diseases and Allergy, Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada

Allergic individuals rarely present with concurrent multiple-organ disease but, rather, with manifestations that privilege a specific site such as the lung, skin, or gastrointestinal tract. Whether the site of allergic sensitization influences the localization of Th2 immune-inflammatory responses and, ultimately, the organ-specific expression of disease, remains to be determined. In this study, we investigated whether both the site of initial Ag exposure and concomitant Th2 differentiation in specific lymph nodes (LNs) privileges Th2 memory responses to mucosal and nonmucosal sites, and whether this restriction is associated with a differential expression in tissue-specific homing molecules. In mice exposed to Ag (OVA) via the peritoneum, lung, or skin, we examined several local and distal LNs to determine the site of Ag-specific proliferation and Th2 differentiation. Whereas respiratory and cutaneous Ag exposure led to Ag-specific proliferation and Th2 differentiation exclusively in lung- and skin-draining LNs, respectively, Ag delivery to the peritoneum evoked responses in gut-associated, as well as distal thoracic, LNs. Importantly, only mice that underwent Th2 differentiation in thoracic- or gut-associated LNs mounted Th2 immune-inflammatory responses upon respiratory or gastric Ag challenge, respectively, whereas cutaneous Th2 recall responses were evoked irrespective of the site of initial sensitization. In addition, we observed the differential expression of gut homing molecules (CCR9, ₄, β₇) in gut-associated LNs and, unexpectedly, a universal induction of skin-related homing molecules (CCR4, CCR10) in all LNs. These data suggest that the site of initial Th2 differentiation and differential homing molecule expression restricts Th2 immune-inflammatory responses to mucosal, but not cutaneous, tissues.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Canadian Institutes for Health Research (CIHR). D.A. and R.F. were supported by CIHR Doctoral Research Awards. M.J. holds a CIHR-Canada Research Chair.

² Address correspondence and reprint requests to Dr. Manel Jordana, Department of Pathology and Molecular Medicine, Division of Respiratory Diseases and Allergy, Centre for Gene Therapeutics, McMaster University, Michael G. DeGroote Centre for Learning and Discovery, Room 4013, 1200 Main Street, West, Hamilton, Ontario, L8N 3Z5, Canada. E-mail address: jordanam{at}mcmaster.ca

³ Abbreviations used in this paper: GI, gastrointestinal; DC, dendritic cell; LN, lymph node; GALT, gut-associated lymphoid tissue; Ad, adenoviral; PB, peripheral blood; BAL, bronchoalveolar lavage; GG, gene gun.