Identification of sex-specific altered T cell immunity in response to prenatal stress in a murine influenza A infection model

Prenatal adverse environmental factors such as maternal stress can impair fetal immune development. This can result in an increased risk for infectious diseases in postnatal life. Emerging evidence arising from epidemiological studies supports that several infectious diseases i.e. influenza A virus (IAV) infections show a strong sex bias. In this study, we aim to investigate how the exposure to prenatal stress affects the offspring´s T cell immunity during an influenza infection. Therefore, pregnant mice have been exposed to stress on four consecutive days during pregnancy (stress group) or left undisturbed (controls). At 9-10 weeks of age, male and female offspring of both groups were infected with influenza A H1N1 virus. On day 3, 6 and 14 post infection, lungs and lung draining lymph nodes were harvested and analyzed by multicolor flow cytometry. In response to prenatal stress, non-infected female offspring showed significantly increased frequencies of interferon-gamma producing T cells as well as the increased expression of CD107a in lymph nodes, compared to prenatally-stressed male offspring. Irrespective of prenatal stress, influenza infection resulted in an earlier and greater weight loss in female offspring compared to males, indicating a more severe course of disease. Taken together our data indicate that a prenatal exposure to stress leads to an increased proinflammatory state predominantly in female offspring. However, this type 1 response does not seem to mitigate the course of disease. Hence, the more severe course of disease seen in female offspring may result from an overshooting, cytokine storm-like response.