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Intraepithelial lymphocytes (IELs) expressing the γδ TCR (γδ IELs) provide continuous surveillance of the intestinal epithelium. However, the mechanisms regulating the basal motility of these cells within the epithelial compartment have not been well defined. We investigated whether IL-15 contributes to γδ IEL localization and migratory behavior in addition to its role in IEL differentiation and survival. Using advanced live cell imaging techniques in mice, we find that compartmentalized overexpression of IL-15 in the lamina propria shifts the distribution of γδ T cells from the epithelial compartment to the lamina propria. This mislocalization could be rescued by epithelial IL-15 overexpression, indicating that epithelial IL-15 is essential for γδ IEL migration into the epithelium. Furthermore, in vitro analyses demonstrated that exogenous IL-15 stimulates γδ IEL migration into cultured epithelial monolayers, and inhibition of IL-2Rβ significantly attenuates the basal motility of these cells. Intravital microscopy showed that impaired IL-2Rβ signaling induced γδ IEL idling within the lateral intercellular space, which resulted in increased early pathogen invasion. Similarly, the redistribution of γδ T cells to the lamina propria due to local IL-15 overproduction also enhanced bacterial translocation. These findings thus reveal a novel role for IL-15 in mediating γδ T cell localization within the intestinal mucosa and regulating γδ IEL motility and patrolling behavior as a critical component of host defense., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Celiac disease is a human T cell-mediated autoimmune-like disorder caused by exposure to dietary gluten in genetically predisposed individuals. This review will discuss how CD4 T cell responses directed against an exogenous Ag can cause an autoreactive B cell response and participate in the licensing of intraepithelial lymphocytes to kill intestinal epithelial cells. Furthermore, this review will examine the mechanisms by which intraepithelial cytotoxic T cells mediate tissue destruction in celiac disease., (Copyright © 2017 by The American Association of Immunologists, Inc.)

The NKG2 family of NK receptors includes activating and inhibitory members. With the exception of the homodimer-forming NKG2D, NKG2 receptors recognize the nonclassical MHC class I molecule HLA-E, and they can be subdivided into two groups: those that associate with and signal through DAP12 to activate cells, and those that contain an ITIM motif to promote inhibition. The function of NKG2 family member NKG2E is unclear in humans, and its surface expression has never been conclusively established, largely because there is no Ab that binds specifically to NKG2E. Seeking to determine a role for this molecule, we chose to investigate its expression and ability to form complexes with intracellular signaling molecules. We found that NKG2E was capable of associating with CD94 and DAP12 but that the complex was retained intracellularly at the endoplasmic reticulum instead of being expressed on cell surfaces, and that this localization was dependent on a sequence of hydrophobic amino acids in the extracellular domain of NKG2E. Because this particular sequence has emerged and been conserved selectively among higher order primates evolutionarily, this observation raises the intriguing possibility that NKG2E may function as an intracellular protein., (Copyright © 2014 by The American Association of Immunologists, Inc.)

Deficiencies of the T cell and NK cell CD3ζ signaling adapter protein in patients with cancer and autoimmune diseases are well documented, but mechanistic explanations are fragmentary. The stimulatory NKG2D receptor on T and NK cells mediates tumor immunity but can also promote local and systemic immune suppression in conditions of persistent NKG2D ligand induction that include cancer and certain autoimmune diseases. In this paper, we provide evidence that establishes a causative link between CD3ζ impairment and chronic NKG2D stimulation due to pathological ligand expression. We describe a mechanism whereby NKG2D signaling in human T and NK cells initiates Fas ligand/Fas-mediated caspase-3/-7 activation and resultant CD3ζ degradation. As a consequence, the functional capacities of the TCR, the low-affinity Fc receptor for IgG, and the NKp30 and NKp46 natural cytotoxicity receptors, which all signal through CD3ζ, are impaired. These findings are extended to ex vivo phenotypes of T and NK cells among tumor-infiltrating lymphocytes and in peripheral blood from patients with juvenile-onset lupus. Collectively, these results indicate that pathological NKG2D ligand expression leads to simultaneous impairment of multiple CD3ζ-dependent receptor functions, thus offering an explanation that may be applicable to CD3ζ deficiencies associated with diverse disease conditions.

We analyzed the autologous NK cell interaction with gliadin-presenting dendritic cells. Gliadin is the known Ag priming the celiac disease (CD) pathogenesis. We demonstrate that gliadin prevents immature dendritic cells (iDCs) elimination by NK cells. Furthermore, cooperation between human NK cells-iDCs and T cells increases IFN-gamma production of anti-gliadin immune response. Gliadin fractions were analyzed for their capability to stabilize HLA-E molecules. The alpha and omega fractions conferred the protection from NK cell lysis to iDCs and increased their HLA-E expression. Gliadin pancreatic enzyme digest and a peptide derived from gliadin alpha increased HLA-E levels on murine RMA-S/HLA-E-transfected cells. Analysis of HLA-E expression in the small intestinal mucosa of gluten-containing diet celiac patients and organ culture experiments confirmed the in vitro data.

Unlike primary T cells in lymph nodes, effector CD8(+) CTL in tissues do not express the costimulatory receptor CD28. We report that NKG2D, the receptor for stress-induced MICA and MICB molecules expressed in the intestine, serves as a potent costimulatory receptor for CTL freshly isolated from the human intestinal epithelium. Expression and function of NKG2D are selectively up-regulated by the cytokine IL-15, which is released by the inflamed intestinal epithelium. These findings identify a novel CTL costimulatory pathway regulated by IL-15 and suggest that tissues can fine-tune the activation of effector T cells based on the presence or absence of stress and inflammation. Uncontrolled secretion of IL-15 could lead to excessive induction of NKG2D and thus contribute to the development of autoimmune disease by facilitating the activation of autoreactive T cells.