The impact of aging and thymus regeneration on tissue-resident CD8 T cell responses to viral lung infection and vaccination

Summary The novel coronavirus, SARS-CoV-2, and the resulting Coronavirus Infectious Disease 2019 (COVID-19) has caused more than 500,000 deaths in the US. COVID-19 causes increased mortality and morbidity in patients over 65 years of age relative to younger patients. This is consistent with well-characterized age-associated decreases in responsiveness to viral infections such as SARS-1, MERS, and West Nile Virus. Likewise, responsiveness to vaccines for these viruses decline in the elderly. Therefore, approaches to enhance vaccine responsiveness in the elderly are critical to protect the most vulnerable population. A major contributor to the loss of immunocompetence with age is the atrophy of the thymus, the primary site of T cell maturation. Production of new naïve T cells depends on the availability of lymphopoietic niches within the thymic microenvironment. Since each T cell generally has one TCR specificity, the narrowing of the naïve T cell repertoire that results from thymic atrophy restricts the magnitude of the T cell response to new infections by reducing the number of naïve T cells capable of mounting a robust response against a given antigen. A well-known example is the loss of CD8 T cells recognizing an immunodominant influenza in the spleen and lungs during aging in mice. Likewise, recent work suggests loss of naïve T cells increases COVID-19 severity in elderly patients. Loss of naïve T cells specific for immunodominant epitopes may be exacerbated by dysfunction of the aged naïve T cells that do persist in older animals. For example, dysfunctional NP366-374-specific tissue-resident memory T cell (Trm) responses, which were suggested to arise as a result of thymus atrophy, were recently shown to promote persistent lung inflammation and exacerbate lung damage during viral pneumonia at 60 days post infection (d.p.i.) in aged mice. The thymus retains a remarkable capacity to regenerate, and regeneration increases the number of flu-specific T cells in aged spleen, however, it is not known whether thymic regeneration affects T cell responses in the lung, survival, or vaccine efficacy for flu, or other viral pathogens. Given the recently revealed role for Trm in age- associated viral pneumonia, and their potential role mediating vaccine responses, it is also important to understand whether thymic regeneration impacts the Trm population in aged lungs. We will evaluate the effect of thymus regeneration (mediated by Growth Hormone (GH) administration, an approach currently used in ongoing human clinical trials) on vaccine-mediated protection from viral pneumonia and secondary CD8 T cell responses using the well-characterized mouse-adapted flu model. As a second model, we have generated an experimental vaccine based on MVA (Modified Vaccinia Ankara) to be used for immunization ahead of infection with mouse- adapted SARS-CoV-2.