Negative Influence of Aging on Differentiation and Proliferation of CD8(+) T-Cells in Dogs

SIMPLE SUMMARY: Immunosenescence is known as changes in the immune system associated with aging and is said to be an important factor for cancer development and the therapeutic effect of cancer immunotherapy in humans. With the recent extension of the dog lifespan, cancer has become the leading cause of death in dogs; therefore, it is necessary to understand immune senescence in dogs. However, it is not well understood how aging impacts the differentiation status and cell proliferation of canine CD8(+) T-cells, which play an important role in cancer immunity. In this study, we aimed to determine which subsets of canine CD8(+) T-cells were influenced by aging and their proliferative potential. We stimulated CD8(+) T-cells from older dogs using antibody-coated beads and interleukin-2 (IL-2) and found that the differentiation of central memory subsets into effectors was enhanced in older CD8(+) T-cells, and the proliferative capacity of both effector and central memory T-cells was decreased. These results suggest that conventional stimulation with T-cell receptor ligands and IL-2 might not be sufficient for culturing T-cells from older dogs. Therefore, the selection of a less differentiated population or modifications of cytokine signaling might be needed to expand older dog CD8(+) T-cells. ABSTRACT: Immunosenescence is an age-related change in the immune system characterized by a reduction in naïve T-cells and an impaired proliferative capacity of CD8(+) T-cells in older individuals. Recent research revealed the crucial impact of immunosenescence on the development and control of cancer, and aging is one of the causes that diminish the therapeutic efficacy of cancer immunotherapies targeting CD8(+) T-cell activation. Despite dog cancer being defined as an age-related disease, there are few fundamental understandings regarding the relationship between aging and the canine immune system. Therefore, we aimed to elucidate the characteristics of immunosenescence in dogs and analyzed the effects of aging on the differentiation status and proliferation of canine CD8(+) T cells using T-cell specific stimulation with anti-canine CD3/CD28 antibody-coated beads and interleukin-2. As a result, we found that older dogs have a lower proliferative capacity of CD8(+) T-cells and a reduction in the naïve subset in their peripheral blood. Further analysis showed that older dogs had attenuated proliferation of the effector and central memory subsets. These results indicate the importance of maintaining less differentiated subsets to expand CD8(+) T-cells in dogs and provide helpful insight into the development of dog immune therapies that require T-cell expansion ex vivo.