CD4 T cells are critical for generating high quality, robust immune responses to influenza infection. Age-related changes, however, compromise the ability of CD4 T cells to differentiate into functional subsets resulting in a multitude of dysregulated responses including delayed viral clearance and prolonged inflammation during influenza infection. The Haynes laboratory has shown that aged nave CD4 T cells exhibit numerous intrinsic defects including significantly reduced proliferation and production of IL-2 in response to antigenic stimulation. Moreover, the ability of aged influenza-specific CD4 T cells to differentiate into highly functional T follicular helper (Tfh) and type 1 helper (Th1) cells is also significantly impaired. Apart from T cell intrinsic changes, it is clear that extrinsic factors in the aged microenvironment are a major contributor to impaired T cell function during aging. Using an adoptive transfer approach, we have shown that the aged environment significantly impacts young T cell proliferation, expansion and differentiation. In addition, young CD4 T cells transferred into aged hosts express higher levels of the regulatory T cell (Treg) associated transcription factor Foxp3 when compared to those transferred into young hosts. It is therefore critical that we examine factors within the aged environment that may contribute to functional defects in CD4 T cells. One of the hallmarks of aging is the accumulation of senescent cells. In this project, we will explore the impact of the senescent environment on CD4 T cell function. Cellular senescence refers to the irreversible growth arrest that occurs when cells experience potentially oncogenic insults. Most importantly, the number of senescent cells increases with chronological aging as accumulation surpasses the rate of elimination by phagocytic cells. Factors secreted by senescent cells can have a direct impact on surrounding cells driving dysfunction and age-related pathologies. Interestingly, many of these factors are cytokines that drive type 2 helper (Th2), memory, and regulatory CD4 T cell differentiation. The impact of senescent cells on immune cell function in this context has not yet been studied. It has been shown, however, that deletion of these cells attenuates the progression of many age related-disorders. Thus, the goal of this proposal will be to examine the effects of senescent cells on CD4 T cell effector functions. Our overall hypothesis is that senescent cells alter CD4 T cell helper subset differentiation and effector function. Furthermore, we predict that ablation of senescent cells in aged mice will significantly improve these age-related CD4 T cell decrements and promote a more robust effector CD4 T helper cell response to influenza infection.
Our published studies have shown that the aged microenvironment has a detrimental impact on the response of adoptively transferred young CD4 T cells. This R21 proposal will examine (1) if senescent cells can impact CD4 T cell priming, activation and differentiation and (2) if deleting senescent cells can improve the immune response to influenza infection.
