Trans-Presentation of IL-15 by Intestinal Epithelial Cells Drives Development of CD8αα IELs

Abstract

IL‐15, which is trans‐presented by IL‐15Rα+ cells to neighboring IL‐2Rβ/γC+ cells, is crucial for the development of intestinal intraepithelial lymphocytes (IEL). Parenchymal cells have a major role in the trans‐presentation of IL‐15 to IELs; however, the specific identity of this cell type is unknown. Since trans‐presentation requires cell‐cell contact, we hypothesize that intestinal epithelial cells (IEC) are the parenchymal cell trans‐presenting IL‐15 to IELs. To determine whether IECs trans‐present IL‐15 to developing IELs, we developed a mouse model with IL‐15Rα expressed exclusively by the IECs. This model was generated by driving IL‐15Rα under the Villin promoter and crossing to the IL‐15Rα−/− background. Analysis of these transgenic mice detected high levels of IL‐15Rα by the IECs. Among the IELs, Thy1‐ CD8αα TCRαβ and TCRγδ subsets were restored to normal or higher levels as compared to control and IL‐15Rα−/− mice. The increases in cell number did not appear to be the result of cell expansion as no differences in proliferation rate was detected among transgenic, control, or IL‐15Rα−/− mice. Collectively, this study demonstrates that IL‐15Rα expression by IECs alone is completely sufficient to direct all the IL‐15‐mediated events driving the development of CD8αα IELs. This research is supported by NIH grant AI070910 and the MDACC Trust Fellowship.

The ARNT–STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells

“…4b) in the Arnt f/f -CD4 and control mice. IL-15 is a critical cytokine for the development of IELs 13,18,19 . Previous studies indicated that treatment of CD4 À CD8 À TCRb þ NK1.1 À B220 À CD5 þ cells with IL-15 increased the expression of CD8aa 19,20 .…”

“…IL-15 is critical for the development of TCRab þ CD8aa þ IELs 18,19 . The role of IL-15 in the development of TCRab þ CD8aa þ IELs was suggested by the observation that IL-15 could support the expression of CD8a by the precursors of TCRab þ CD8aa þ IELs in vitro 19,20,23 .…”

Intra- and Intercompartmental Movement of γδ T Cells: Intestinal Intraepithelial and Peripheral γδ T Cells Represent Exclusive Nonoverlapping Populations with Distinct Migration Characteristics

“…We hypothesized that mouse epithelial or keratinocyte cell lines could replace such cell-cell contacts, and may provide a microenvironment that supports gd iIEL survival ex vivo. To test this hypothesis, we cocultured GFP high gd iIELs either with the intestinal epithelial cell line m-IC (cl2) or with the keratinocyte cell line PDV for a period of 7 d. Furthermore, GFP high gd iIELs were cultured with a mixture of the cytokines IL-2, IL-7, and IL-15, which have been reported to at least slightly prolong the ex vivo life span of isolated gd iIELs (26,27,(53)(54)(55)(56)(57). By FACS quantification of GFP + cells it quickly became evident that m-IC (cl2) cells were not supporting the ex vivo survival of sorted gd iIELs (Fig.…”

Thymic and peripheral microenvironments differentially mediate development and maturation of iNKT cells by IL-15 transpresentation

“…The opposing cells respond through the signaling components of an IL-15 receptor complex (IL-15R␤/␥C). 30 Despite studies identifying IL-15 transpresenting cells for NK, memory CD8 ϩ T cells, and intestinal intraepithelial lymphocytes, [31][32][33] the cell type(s) transpresenting IL-15 to iNKT cells has not been described. Prior studies using various IL-15R␣ bone marrow (BM) chimeras revealed IL-15R␣ expression by either hematopoietic or nonhematopoietic cells partially recovers peripheral NK1.1 ϩ T cell numbers.…”