Deficiencies in Gut NK Cell Number and Function Precede Diabetes Onset in BB Rats

Abstract

Defects in the intestinal immune system may contribute to the pathogenesis of autoimmune diseases. Intraepithelial lymphocytes represent a substantial fraction of gut-associated lymphocytes, but their function in mucosal immunity is unclear. A newly described population of NK cells that spontaneously secrete IL-4 and IFN-γ is present in the intraepithelial lymphocyte compartment of the rat. We hypothesized that defects in the number or function of these cells would be present in rats susceptible to autoimmunity. We report that the number of NKR-P1A+CD3− intraepithelial NK (IENK) cells is deficient before onset of spontaneous autoimmune diabetes in diabetes-prone BB (BBDP) rats. The absolute number of recoverable IENK cells was only ∼8% of that observed in WF rats. Bone marrow transplantation from histocompatible WF donors reversed the IENK cell deficiency (and prevented diabetes) in these animals, suggesting a hemopoietic origin for their IENK cell defect. Analysis of diabetes-resistant BB rats, which develop autoimmune diabetes only after perturbation of the immune system, revealed IENK cell numbers intermediate between that of BBDP and WF rats. IENK cells were selectively depleted during treatment to induce diabetes. Prediabetic BBDP and diabetes-resistant BB animals also exhibited defective IENK cell function, including decreased NK cell cytotoxicity and reduced secretion of IL-4 and IFN-γ. IENK functional defects were also observed in LEW and BN rats, which are susceptible to induced autoimmunity, but not in WF, DA, or F344 rats, which are resistant. Defects in IENK cell number and function may contribute to the pathogenesis of autoimmune diseases including type 1 diabetes.

All-transRetinoic Acid Inhibits Type 1 Diabetes by T Regulatory (Treg)-Dependent Suppression of Interferon-γ–Producing T-cells Without Affecting Th17 Cells

“…Previous studies have suggested that Treg cells do not interact directly with Teff cells; instead, they may suppress target Teff cells through the interaction with antigen-presenting cells (40,41). Our results do not exclude the possible involvement of, for example, dendritic natural killer T-cells and natural killer cells, which have been suggested to play a role during islet inflammation and diabetes onset (27,(42)(43)(44)(45)(46). Further studies are needed to determine the relative contribution of these different possibilities.…”

Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5

“…[30][31][32] Gimap5 deficiency interfered with virtually all stages of mouse NK development and was incompatible with NK formation in any of the anatomic compartments thought to provide a permissive environment for NK maturation, including BM, spleen, lymph nodes, and liver. The presence of a small number of V␣ TCR-positive invariant NKT (iNKT) cells (as defined by ␣-GalCer/CD1d staining) indicates that some of these cells can develop and successfully rearrange their TCR chains.…”

Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats

“…These cells lie in close proximity to the intestinal epithelial barrier and facilitate immune responsiveness, especially in the presence of elevated intestinal epithelial permeability (6). Recent reports suggest that quantitative and͞or qualitative deficiencies in a subset of NK cells occur in several autoimmune diseases, including type 1 diabetes (T1D) (7) and celiac disease (CD) (8). These cells play a pivotal role in the maintenance of immune tolerance by down-regulating the immune response to foreign antigens when they gain access beyond the intestinal mucosal barrier (6).…”