IL-15-Dependent Activation-Induced Cell Death-Resistant Th1 Type CD8αβ+NK1.1+ T Cells for the Development of Small Intestinal Inflammation

Abstract

To clarify the role of IL-15 at local sites, we engineered a transgenic (Tg) mouse (T3b-IL-15 Tg) to overexpress human IL-15 preferentially in intestinal epithelial cells by the use of T3b-promoter. Although IL-15 was expressed in the entire small intestine (SI) and large intestines of the Tg mice, localized inflammation developed in the proximal SI only. Histopathologic study revealed reduced villus length, marked infiltration of lymphocytes, and vacuolar degeneration of the villus epithelium, beginning at ∼3–4 mo of age. The numbers of CD8+ T cells, especially CD8αβ+ T cells expressing NK1.1, were dramatically increased in the lamina propria of the involved SI. The severity of inflammation corresponded to increased numbers of CD8αβ+NK1.1+ T cells and levels of production of the Th1-type cytokines IFN-γ and TNF-α. Locally overexpressed IL-15 was accompanied by increased resistance of CD8αβ+ NK1.1+ T cells to activation-induced cell death. Our results suggest that chronic inflammation in the SI in this murine model is mediated by dysregulation of epithelial cell-derived IL-15. The model may contribute to understanding the role of CD8+ T cells in human Crohn’s disease involving the SI.

Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity

“…In addition, the cytokine milieu during the priming may be one of the major factors that determine the life and quality of memory CD8 ϩ T cells. Although IL-15 inhibits activationinduced cell death (7,37), this cannot explain the long-term effects, because animals that received either VV-IL-2 or VV-IL-15 cleared virus within 1 or 2 weeks, and therefore long-term expression of cytokines by vaccinia cannot be involved.…”

Interleukin‐15 prevents concanavalin A‐induced liver injury in mice via NKT cell‐dependent mechanism†

“…28,29 IL-15 contributes to the pathogenesis of these autoimmune diseases through (1) recruiting and activating T cells to the inflammatory tissue; (2) leading to TNF-␣ and IFN-␥ secretion by autoreactive T cells; and (3) protecting autoreactive T cells from apoptosis. 30,31 On the contrary, in Con A model, IL-15 administration neither recruited more lymphocytes into liver nor protected NKT cells from apoptosis (Fig. 3A).…”

Role of STAT3 in inflammatory bowel disease

“…However, as the receptors of these cytokines and growth factors are present on both innate and acquired cells, activation of STAT3 is likely to occur in both cell types [5,14,[34][35][36]57,58] . Therefore, as the function of STAT3 is a double-edged sword, careful attention should be directed toward the cell population that is being targeted when one contemplates STAT3 inhibition or activation in human IBD [59] .…”

“…Among these, roles of IL-6, IL-11, IL-15, HGF, GH and leptin in experimental colitis have been demon strated [9][10][11][12][33][34][35][36] . For example, IL-6, IL-15 and leptin play a pathogenic role in colitis by activating STAT3 predominantly in the acquired immune cells [9,10,12,36,37] (Figure 1).…”