Sci. STKE, 21 September 2004
IMMUNOLOGY NKG2D: Straddling the Innate and Adaptive Boundary
Hüe et al. and Meresse et al. uncovered evidence for T cell receptor (TCR)-independent T cell cytolytic activity mediated through NKG2D. Celiac disease, a malabsorption disorder of the small intestine triggered by gluten (a protein found in wheat, rye, and barley), is associated with infiltration of the intestinal mucosa by T cells and villous atrophy (see Sollid). NKG2D, an activating receptor found in natural killer cells, also acts as a TCR costimulator in cytotoxic T cells. Its ligands MICA and MICB (MHC class I-related chains A and B) are expressed in intestinal epithelial cells, and their abundance is increased in response to stress. Both groups observed that MIC was overexpressed in intestinal epithelia of patients with active celiac disease. Hüe et al. found that, in patients with inactive disease, MICA expression was stimulated by the gluten component gliadin by way of interleukin 15 (IL-15) (which is overexpressed in celiac disease). In T cell lines derived from celiac patients' intraepithelial lymphocytes (IELs), NKG2D activation stimulated TCR-dependent target cell lysis and, in severe disease, directly stimulated T cell cytotoxicity. Meresse et al. found that exposure of freshly isolated IELs from individuals without celiac disease to IL-15 increased the abundance of NK2GD and enabled NKG2D-dependent cytolysis, whereas IELs from patients with active celiac disease had high levels of NKG2D and cytolytic behavior without IL-15 treatment. Using a combination of pharmacological and Western analysis, the latter group showed that activation of phosphoinositide 3-kinase (PI3K), extracellular signal-regulated protein kinase (ERK), and Jun N-terminal kinase (JNK) was required for NK2GD-dependent cytolysis and that IL-15 promoted PI3K-dependent phosphorylation of ERK. Thus, both groups suggest that the villous atrophy seen in celiac disease is mediated through T cell-mediated destruction of intestinal epithelial cells, which depends on IL-15-dependent stimulation of MIC-NKG2D signaling and can occur independently of TCR activation.
S. Hüe, J.-J. Mention, R. C. Monteiro, S. Zhang, C. Cellier, J. Schmitz, V. Verkarre, N. Fodil, S. Bahram, N. Cerf-Bensussan, S. Caillat-Zucman, A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease. Immunity 21, 367-377 (2004). [Online Journal]
B. Meresse, Z. Chen, C. Ciszewski, M. Tretiakova, G. Bhagat, T. N. Krausz, D. H. Raulet, L. L. Lanier, V. Groh, T. Spies, E. C. Ebert, P. H. Green, B. Jabri, Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21, 357-366 (2004). [Online Journal]
L. V. Sollid, Intraepithelial lymphocytes in celiac disease: License to kill revealed. Immunity 21, 303-304 (2004). [Online Journal]
Citation: NKG2D: Straddling the Innate and Adaptive Boundary. Sci. STKE 2004, tw336 (2004).
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