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NKG2D-Dependent IL-17 Production by Human T Cells in Response to an Intracellular Pathogen¹

Padmaja Paidipally^*,, Sivakumar Periasamy^*,, Peter F. Barnes^*,,, Rohan Dhiman^*,, Mohanalaxmi Indramohan^*,, David E. Griffith, David Cosman and Ramakrishna Vankayalapati^2,*,

^* Center for Pulmonary and Infectious Disease Control, and Departments of Microbiology and Immunology and Medicine, University of Texas Health Center, Tyler, TX 75708; and Amgen, Seattle, WA 98101

We studied the factors that control IL-17 production in human Mycobacterium tuberculosis infection. CD4⁺ cells from healthy tuberculin reactors produced IL-17 in response to autologous M. tuberculosis-stimulated monocytes, and most IL-17⁺ cells were Ag experienced, CD4⁺CD62L^–. IL-17 production by CD4⁺ cells was inhibited by anti-IL-23, but not by Abs to IL-1, IL-6, or TGF-β. Anti-NKG2D reduced IL-17 production and the frequency of CD4⁺CD62^– IL-17⁺ cells, suggesting that NKG2D stimulates IL-17 production. CD4⁺NKG2D⁺ cells did not produce IL-17. Monocytes and alveolar macrophages from healthy donors produced IL-23 in response to M. tuberculosis. Addition of CD4⁺ cells markedly enhanced IL-23 production by M. tuberculosis-stimulated monocytes, and this was inhibited by anti-NKG2D and by Abs to UL-16 binding protein (ULB)1, a ligand for NKG2D on APCs. We conclude that binding of NKG2D to UL-16 binding protein (ULB)1 contributes to IL-23-dependent IL-17 production by CD4⁺ cells in human M. tuberculosis infection.

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 grants from the National Institutes of Health (AI054629, AI073612, and A1063514), the James Byers Cain Research Endowment, and the Center for Pulmonary and Infectious Disease Control. P.F.B. holds the Margaret E. Byers Cain Chair for Tuberculosis Research.

² Address correspondence and reprint requests to Dr. Ramakrishna Vankayalapati, Center for Pulmonary and Infectious Disease Control, University of Texas Health Center, 11937 U.S. Highway 271, Tyler, TX 75708-3154. E-mail address: krishna.vankayalapati{at}uthct.edu