A diverse T cell repertoire is essential for a vigorous immune response to new infections, and decreasing repertoire diversity has been implicated in the age-associated decline in CD8 T cell immunity. In this study, using the well-characterized mouse infl uenza virus model, we show that although comparable numbers of CD8 T cells are elicited in the lung and lung airways of young and aged mice after de novo infection, a majority of aged mice exhibit profound shifts in epitope immunodominance and restricted diversity in the TCR repertoire of responding cells. A preferential decline in reactivity to viral epitopes with a low naive precursor frequency was observed, in some cases leading to " holes " in the T cell repertoire. These effects were also seen in young thymectomized mice, consistent with the role of the thymus in maintaining naive repertoire diversity. Furthermore, a decline in repertoire diversity generally correlated with impaired responses to heterosubtypic challenge. This study formally demonstrates in a mouse infection model that naturally occurring contraction of the naive T cell repertoire can result in impaired CD8 T cell responses to known immunodominant epitopes and decline in heterosubtypic immunity. These observations have important implications for the design of vaccine strategies for the elderly.

Nonhuman primate (NHP) models will expedite therapeutics and vaccines for COVID-19 into clinical trials. We compared acute SARS-CoV-2 infection in young and old rhesus macaques and baboons and old marmosets. Macaques had clinical signs of viral infection, mild-to-moderate pneumonitis and extra-pulmonary pathologies; both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage (BAL) was increased in old versus young baboons. Using techniques like CT imaging, immunophenotyping, alveolar/peripheral cytokine responses and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent Type I-interferon response. Macaques developed T cell memory phenotype/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.

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Generation of effective T helper cell type 1 (Th1) responses are required for immunity against intracellular bacteria. However, some intracellular bacteria require Interleukin (IL)-17 to drive Th1 immunity and subsequent protective host immunity. Here, in a model of Mycobacterium bovis Bacille Calmette Guerin (BCG) vaccination in mice, we demonstrate that the dependence on IL-17 to drive Th1 responses is a host mechanism to overcome bacteria-induced IL-10 inhibitory effects. We show that BCG-induced Prostaglandin-E2 (PGE2) promotes the production of IL-10 which limits Th1 responses, while simultaneously inducing IL-23 and Th17 differentiation. The ability of IL-17 to down-regulate IL-10 and induce IL-12 production allows the generation of subsequent Th1 responses. Accordingly, BCG-induced Th17 responses precedes generation of Th1 responses in vivo, while absence of IL-23 pathway decreases BCG vaccine-induced Th17 and Th1 immunity and subsequent vaccine-induced protection upon M.tuberculosis challenge. Importantly, in the absence of IL-10, BCG-induced Th1 responses occurs in an IL-17-independent manner. These novel data project the IL-23/IL-17 pathway in driving Th1 responses, specifically, to overcome IL-10 mediated inhibition and that in absence of IL-10, the generation of BCG induced Th1 immunity is IL-17-independent.

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