Effect of senescent cells

Summary The induction and maintenance of adaptive immune responses are critical for effective and durable protection against diverse pathogens and the efficacy of vaccines. Yet it is known that both the homeostasis and function of adaptive immune cells declines with age – while there may be multiple causes for this, recent

studies (including those from our group) indicate a potentially pivotal role for senescent cells. Diverse cell types (including immune cells) become senescent with age and in various chronic disease states, and this state not only affects the replicative potential of the senescent cells (SnC) themselves, but by their production

of a variety of factors (in what is termed the senescence-associated secretory phenotype or SASP), they can affect other cells, in trans. Many of these SASP factors are pro-inflammatory and can provoke immunopathology in vulnerable populations (including the aged, as illustrated in the cytokine storm reported in

elderly COVID-19 patients). These “bystander” effects have been demonstrated in experimental mouse models. Most exciting, ablation of SnC (using senotherapeutic compounds) results in marked improvement of immune control of pathogens. However, there is a key knowledge gap in understanding what effect SnCs

have on adaptive immune populations, how those effects are mediated and how crosstalk between senescent and immune cells influences the physiological establishment of senescence with age. We address these in three Specific Aims. Aim 1 tests how exposure to SnC – as a single variable – influences adaptive immune cell

homeostasis and function in response to defined viral infections, using well defined mouse models to pinpoint the consequences of SnC introduction vs destruction on naïve and memory T and B cell populations. This includes functional and single-cell analysis approaches. In Aim 2, we turn the tables by investigating tantalizing

data which indicate certain immune populations (including NK cells) may be capable of SnC destruction during normal physiology – a feedback loop that we suspect is compromised with age, resulting in SnC build up. The function of NK cells and other immune populations in culling SnC will be explored. Aim 3 explores how SnC

mediate their inhibitory effects on lymphocytes – by harnessing the power of CRISPR/Cas9 approaches to ablate receptors for SASP factors and explore the functional significance of immunoregulatory molecules induced on “young” T cells in the aged environment, as well as test the ability of SASP factors to provoke these

age-related changes, in vitro in both mouse and human cells. The approaches and goals integrate with the single-cell studies, novel mouse model development and refinement of senotherapeutics conducted in Project 1, and with complementary studies on generation, homeostasis and function of adaptive immune cells

embedded in non-lymphoid tissues, conducted in Project 3. A consistent source of the key mouse models and pathogens used will be provided by Core B, while all the single-cell analysis from Project 2 and the other Projects will be conducted and integrated by Core C. The Administrative Core (Core A) will oversee

coordinated work of Projects and Cores and establish internal and external review.