Characterization of ENU-Induced Mutant Mice Expressing an Alternatively Spliced IL-15 Reveals Defective Antigen Presentation and CD8+ T Cell Immunity 2256931

Introduction Interleukin-15 (IL-15) is critical for the activation and expansion of CD8+ T cells and dendritic cells (DCs). We investigated the role of an alternatively spliced IL-15 variant, IL-15α”E7, using an ENU-mutagenized mouse line (P191) that exhibits elevated IL-15α”E7 expression. Following HSV-1 infection, CD8+ T cells in P191 mice showed impaired effector function and reduced proliferative capacity compared with wild-type controls. Methods To further define this defect, CTV-labeled gB-T1 transgenic CD8+ T cells, specific for the HSV-1 glycoprotein B (gB) epitope, were adoptively transferred into P191 and wild-type (WT) mice before HSV-1 footpad immunization. Results On day 3 post-immunization, proliferation of gB-T1 cells in the draining popliteal lymph node (LN) was comparable between groups. However, gB-T1 cell numbers in the peripheral LNs of P191 mice were reduced by 2-fold and 4.7-fold relative to wild-type (WT) mice on day 5 and 10, respectively. These findings indicate that IL-15α”E7 expression compromises sustained CD8+ T cell expansion despite normal early activation. Conclusion We hypothesize that IL-15α”E7 attenuates inflammatory responses and limits LN permeability, thereby restricting antigen dissemination and sustained antigen presentation. Alternatively, IL-15α”E7 may shorten DC lifespan, leading to insufficient support for prolonged CD8+ T cell responses. Future studies will employ fluorescent nanodiamonds as antigen mimetics to assess lymphoid permeability and DC expansion kinetics, aiming to elucidate how IL-15α”E7 expression modulates antigen distribution and DC-mediated antiviral immunity.