IL‐15 modulates the balance between Bcl‐2 and Bim via a Jak3/1‐PI3K‐Akt‐ERK pathway to promote CD8αα+ intestinal intraepithelial lymphocyte survival

• Published in: European journal of immunology 2013-09, Vol.43 (9), p.2305-2316
• Main Authors: Lai, Yein‐Gei, Hou, Mau‐Sheng, Lo, Albert, Huang, Shih‐Ting, Huang, Yen‐Wen, Yang‐Yen, Hsin‐Fang, Liao, Nan‐Shih
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; Bcl‐2; Bim; CD8 Antigens - metabolism; CD8αα+ intestinal intraepithelial lymphocytes (iIELs); Cell Survival; Epithelial Cells - metabolism; Extracellular Signal-Regulated MAP Kinases - metabolism; IL‐15; Interleukin-15 - metabolism; Intestines - cytology; Intestines - immunology; Janus Kinase 3 - metabolism; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Receptors, Interleukin-15 - metabolism; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201243026

IL‐15 is an essential survival factor for CD8αα+ intestinal intraepithelial lymphocytes (iIELs) in vitro and in vivo. However, the IL‐15‐induced survival signals in primary CD8αα+ iIELs remains elusive. Although Bcl‐2 level in CD8αα+ iIELs positively correlates with IL‐15Rα expression in the intestinal epithelial cells, overexpression of Bcl‐2 only moderately restores CD8αα+ γδ iIELs in Il15−/− mice. Here, we found that IL‐15 promptly activated a Jak3‐Jak1‐PI3K‐Akt pathway that led to the upregulation of Bcl‐2 and Mcl‐1. This pathway also induced a delayed but sustained ERK1/2 activation, which not only was necessary for the maintenance of Bcl‐2 but also resulted in the phosphorylation of extra‐long Bim at Ser65. The latter event facilitated the dissociation of Bim from Bcl‐2 without affecting Bim abundance in IL‐15‐treated CD8αα+ iIELs. Using an adoptive cell transfer approach, we found that either overexpression of Bcl‐2 or removal of Bim from CD8αα+ iIELs promoted their survival in Il15ra−/− mice. Taken together, IL‐15 promotes CD8αα+ iIEL survival by both increasing Bcl‐2 levels and dissociating Bim from Bcl‐2 through activation of a Jak3‐Jak1‐PI3K‐Akt‐ERK1/2 pathway, which differs from a previously reported IL‐15‐induced survival signal.