ENU-induced C-terminal truncation of Runx3 in mice enhances maintenance of memory T cells through upregulation of IL-15 expression

Abstract

Abstract Immunological memory provides faster and stronger immune responses to protect host from infectious pathogens and tumor cells. T cell memory is a major part of immunological memory, and plays an important role to eliminate tumor cells or cells infected by intracellular pathogen. Cytokines including IL-15, IL-7 and IL-4 have been reported to enhance the generation or maintenance of memory T cells. IL-15 enhances homeostatic proliferation and survival of memory CD8+ T cells. An ENU-affected mouse pedigree carried a Tyr301stop point mutation of Runx3, which resulted in a truncated form of Runx3. These mice started to show spontaneous diarrhea after weaning (spontaneous colitis, SC). SC mice also expressed CD4-derepression in the CD8+ T cells, and loss of memory phenotype CD8+ T cells. SC CD8+ T cells showed proliferation deficiency and decreased memory CD8+ T cell precursors after activation and also had poor response to IL-15-induced proliferation. However, SC host mice enhanced in vivo long-term survival of activated WT CD8+ cells through improvement of homeostatic proliferation. This improvement of homeostatic proliferation was due to elevated serum IL-15 levels. In summary, C-terminal truncated Runx3 in mice results in upregulation of IL-15 expression and provides enhanced homeostatic environment for memory CD8+ T cells; however, CD8+ T cells have intrinsic memory defect. Thus, the SC mouse model is a valuable tool for investigations on the effect of immune system upon spontaneous colitis.