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¹ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
² Pediatric Rheumatology, Children's Hospital and Regional Medical Center, Seattle, WA 98105

CORRESPONDENCE Veronika Groh: vgroh{at}fhcrc.org

The NKG2D receptor stimulates natural killer cell and T cell responses upon engagement of ligands associated with malignancies and certain autoimmune diseases. However, conditions of persistent NKG2D ligand expression can lead to immunosuppression. In cancer patients, tumor expression and shedding of the MHC class I–related chain A (MICA) ligand of NKG2D drives proliferative expansions of NKG2D⁺CD4⁺ T cells that produce interleukin-10 (IL-10) and transforming growth factor-β, as well as Fas ligand, which inhibits bystander T cell proliferation in vitro. Here, we show that increased frequencies of functionally equivalent NKG2D⁺CD4⁺ T cells are inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE), suggesting that these T cells may have regulatory effects. The NKG2D⁺CD4⁺ T cells correspond to a normally occurring small CD4 T cell subset that is autoreactive, primed to produce IL-10, and clearly distinct from proinflammatory and cytolytic CD4 T cells with cytokine-induced NKG2D expression that occur in rheumatoid arthritis and Crohn's disease. As classical regulatory T cell functions are typically impaired in SLE, it may be clinically significant that the immunosuppressive NKG2D⁺CD4⁺ T cells appear functionally uncompromised in this disease.

© 2009 Dai et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Abbreviations used: CBMC, cord blood mononuclear cell; FasL, Fas ligand; IRB, Internal Review Board; LAP, latency-associated peptide; MICA, MHC class I–related chain A; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SLEDAI, SLE disease activity index; sMICA, soluble MICA; T reg cell, regulatory T cell; ULBP, UL16-binding protein.

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