Role of p16 expressing cells in formation and function of T cell memory with age

Abstract

Abstract Aging results in the accumulation of senescent cells that have been shown to cause dysfunction in many contexts but the effect on the function of T cell immunity is still unclear. Here, we aimed to probe the effects of clearing senescent cells on T cell responses to influenza infection. We utilized a powerful p16 trimodality reporter mouse model (p16-3MR) that includes cassettes encoding luciferase, RFP, as well as herpesvirus thymidine kinase (HSV-TK) all under the control of p16 promoter. p16 is commonly upregulated in senescent cells so this model allows us to detect senescent cells via luciferase activity, RFP expression, and selectively delete those cells by treating with ganciclovir (GCV). In aged p16-3MR mice following flu infection, we observed a transient induction of RFP+ p16 expressing cells at two weeks post infection. We hypothesized that p16 expressing cells are important for resolution of inflammation and fostering the effector to memory transition. Aged p16-3MR mice lacking p16 expressing cells following GCV treatment developed fewer flu-specific tissue resident memory CD8 T cells (Trm, CD103+ CD69+) in the lung compared to control treated aged counterparts. Interestingly, deletion of p16 expressing cells also increased the proportion of flu-specific Trm cells in the draining lymph node 30 days post infection. As a result, these mice were less effective in controlling viral burden following a secondary challenge. Conversely, during primary infection, deletion of p16 expressing cells induced a more youthful response in aged mice. This suggests that targeting senescent cells is a double-edged sword that may potentiate primary responses to infection while severely limiting the ability to form durable and protective memory. Supported by grants from NIH (R21 AG060707, R21 AG071292)