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Interleukin-16 Stimulation Results in Recruitment and Potential Induction of De Novo FoxP3+ Treg Cells in the Lungs

¹ Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to William W. Cruikshank, Ph.D., Pulmonary Center, R-304, BUSM, 715 Albany Street, Boston, MA 02118. E-mail: bcruiksh{at}bu.edu

As a natural ligand for CD4, IL-16 has been shown to preferentially induce migration in Th1 cells, and in long-term cultures with IL-2, IL-16 facilitates expansion of CD4+CD25+ cells. In addition, IL-16 has an immunomodulatory role in asthmatic inflammation, as exogenous administration significantly reduces inflammation and airway hyperreactivity. The mechanism for this, however, is not clear. Based on its functional characteristics and potential immunomodulatory role, we investigated the ability of IL-16 to recruit and influence development of T regulatory (Treg) cells. We now demonstrate that IL-16 preferentially induces migration in a CD25+, CTLA-4+ human T cell subset and that responding cells produce IFN- and TGF-β, but no IL-10. These cells are relatively unresponsive to antigenic stimulation and can suppress proliferation and IL-5, but not IFN-, production by autologous T cells. We further demonstrate that IL-16 instillation into Balb/c mice results in a preferential lung recruitment of cells that are Foxp3+. In addition, we show that IL-16 stimulation may facilitate de novo induction of Foxp3+ Treg cells, as stimulation of FoxP3-negative T cells for 48 hours results in expression of FoxP3 mRNA and protein, and further, IL-16 stimulation of Jurkat cells expressing the FoxP3 promoter results in a 15–20-fold induction of promoter activity. These data indicate that at sites of inflammation IL-16 may contribute to selective Treg cell expansion through the preferential induction of a migratory response from existing Treg cells, as well as by the induction of de novo generation of FoxP3+ cells. These findings offer a potential mechanism for the immunosuppressive effects of IL-16 seen in asthma.

FOOTNOTES

Supported by NIH AI35680 (PI, D.M.C.).

Conflict of Interest Statement: C.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.S.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. X.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.M.C. is the scientific founder of Abkine Pharmaceuticals, Inc. and is listed as inventor on several patents related to IL-16. F.F.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.W.C. is the scientific founder of Abkine Pharmaceuticals, Inc. and is listed as inventor on several patents related to IL-16.

(Received in original form July 25, 2008; accepted in final form November 4, 2008)

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by McFadden, C. Articles by Cruikshank, W. W. Search for Related Content PubMed Articles by McFadden, C. Articles by Cruikshank, W. W.