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Come forth CD1d: Hsp110 in the regulation of intestinal epithelial CD1d expression
Christopher V. Nicchitta
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA
Address correspondence to: Christopher V. Nicchitta, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. Phone: (919) 684-8948; Fax: (919) 684-5481; E-mail: c.nicchitta@cellbio.duke.edu.
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Published September 1, 2003 - More info
J Clin Invest. 2003;112(5):646–648. https://doi.org/10.1172/JCI19641.
© 2003 The American Society for Clinical Investigation
Intestinal epithelial cells (IECs) serve as the cellular barrier between the enormously challenging antigenic environment of the intestinal lumen — consisting of dietary antigens, viruses, bacteria, and fungi — and the mucosal immune system, the largest lymphoid tissue of the body. Given this remarkable immunological challenge, it comes as no surprise that both normal and pathological intestinal epithelial physiology involves complex interactions among the immune and nonimmune cells of the gut, the intestinal flora, and the activities of the sympathetic, parasympathetic, and enteric nervous systems. Unfortunately, such complex interactions often go awry, resulting in the chronic, T lymphocyte–mediated mucosal injury that characterizes inflammatory bowel diseases (IBDs).
The molecular etiology of IBDs is under continuing investigation, with current views emphasizing interactions between environmental pathogens and an altered, or genetically permissive, immune system (1). Recent studies have implicated CD1d in the regulation of intestinal inflammation, though here again, the precise immunological mechanism for such regulation remains to be identified (2–4). CD1d is a nonclassical MHC molecule that functions in the development of NK1.1+ T cells and has been implicated in the process of IEC-elicited T cell proliferation (5, 6). Interestingly, antibody cross-linking of CD1d has been demonstrated to elicit epithelial IL-10 production (7). IL-10 is known to serve important functions in the regulation of mucosal inflammation, and, importantly, IL-10–deficient mice coincidentally develop IBD (reviewed in ref. 8). From these observations has come the intriguing suggestion that ligation of CD1d may serve to suppress mucosal inflammation, perhaps via activation of autocrine, IL-10–dependent responses in IECs (7). Such observations point to a critical need to understand the regulation of CD1d expression, CD1d recognition, the antigen(s) presented by IEC CD1d, and potential roles of CD1d-directed signaling in the regulation of mucosal inflammation.
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An autocrine function for Hsp110?
As with all groundbreaking discoveries, the identification of Hsp110 as a potential autocrine inducer of CD1d expression raises many additional questions. To the cell biologist, the existence of substantial quantities of intact Hsp110 in intestinal luminal contents is something of a mystery. As Colgan et al. note, Hsp110 is not found in prokaryotes; therefore gut flora are not the source. A dietary source can be questioned, as it is unlikely that the Hsp110 would be recovered in a structurally intact form in the large intestine. And so the most likely source is the gut epithelium itself. Yet, Hsp110 does not possess a signal peptide and so cannot be secreted from IECs via the classical secretory pathway. Non-canonical secretion, as seen, for example, with FGF-2, is a possibility (14). However, this release pathway, and the analogous pathway in yeast, appear to transport very few proteins. Perhaps, then, Hsp110 is released into the intestinal lumen as a consequence of epithelial renewal, particularly in response to IEL activation (15). If this is the case, though, it might be expected that other abundant cytosolic chaperone proteins, such as Hsp90 and Hsp70, would be recovered in the intestinal contents as well. Nonetheless, perhaps inappropriately elevated levels of Hsp110 in the intestinal lumen serve as an immunological “trigger” leading to aberrant induction of CD1d expression, a subsequent activation of NK T cells, and IL-13–elicited destruction of IECs (Figure 1) (16). Whatever the mechanism, one is left to ponder the fascinating mystery of why IECs might (uniquely?) release Hsp110 into the gut lumen. Insights into the precise cellular source of the gut-lumen Hsp110 and the mechanism of its release will provide all-important clues to this new riddle in the ever-expanding world of Hsp110 function.
Figure 1Hypothetical model for an Hsp110 function in IEC CD1d expression. (I) In this speculative model, Hsp110 release from IECs occurs during the physiological process of epithelial renewal and contributes, directly or indirectly, to the regulation of CD1d expression. In the case of normal (physiological) epithelial cell renewal, Hsp110 is released, whereupon it serves to signal normal (physiological) levels of CD1d expression. In this scenario, CD1d-directed NK T cell activation leads to the induction of IL-4 and IL-10 release and suppression of inflammatory responses. (II) In the case of accelerated (pathological) IEC death, Hsp110 release may be elevated, leading to enhanced levels of CD1d expression and perhaps alterations in the identity or relative quantity of CD1d ligands. In this scenario, NK T cells would be activated to yield release of the proinflammatory cytokines IFN-γ and TNF-α, thereby promoting the induction of inflammatory disease. TCR, T cell receptor.
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