During times of food shortages or malnutrition, organisms devote less energy to defending against infections. Indeed, malnutrition reduces the total number and functionality of specific immune cells. This may result in permanent deficiencies in immune defenses, even after adequate nutrition is restored. Data presented in this project suggest that organisms may have evolved mechanisms to minimize these immune defense deficiencies during malnutrition. This research explores the hypothesis that malnutrition triggers specific immune cells (T cells) to conserve energy to preserve a slightly larger number of immune cells, which ultimately minimizes the deleterious effects of malnutrition. Mice are used as a model organism to test this hypothesis. In the absence of infection, immune cells move in a coordinated fashion throughout the body. This behavior is critical for immune defense and is costly in terms of energy usage. This research will examine if malnourished immune cells disengage from these coordinated patterns of movement. Genetically-altered mice will also be studied to characterize the molecular pathways that may contribute to these energy-saving behaviors. Overall, this project will enable a better understanding of the mechanisms that contribute to the conservation of resources during malnutrition. This information may help researchers understand more about immunity in animals and humans. In addition, high-school Latinas and undergraduate research students will gain career mentorship and technical training related to experimental design, data acquisition and analysis, and scientific communication throughout this project.
It is clear that the activation of the immune response is hindered during malnutrition. However, it is unclear how malnutrition affects the immune system in the absence of infection. The maintenance of a sufficiently large and diverse population of T cells (one type of antigen-specific adaptive immune cell) is critical for the initiation of a functional and appropriate immune response. This research explores a potential mechanism that may preserve a larger population of naïve T cells during short-term malnutrition. The hypothesis is that glucocorticoids act to quickly reduce the total number of peripheral T cells and induce an energy-saving, super-quiescent phenotype in T cells during malnutrition. Thus, this research will determine whether malnutrition reduces the number of naïve T cells via a glucocorticoid-dependent mechanism and if so, whether glucocorticoid upregulation of a particular cell surface receptor (CD127) is involved. Glucocorticoids will be inhibited in wild-type mice using known chemical glucocorticoid inhibitors. Complementary research will use mouse strains that have a conditional deletion of the glucocorticoid receptor in T cells, and mouse strains that have a selective mutation of glucocorticoid response elements upstream of the CD127 gene. These experimental systems will be used to determine if malnutrition eliminates rhythmic circadian T cell migration, reduces T cell migratory speed, redirects naïve T cells to temporarily reside in the bone marrow, or disrupts distinct lymph node entry efficiencies between CD4+ and CD8+ T cells utilizing the adoptive transfer of labeled T cells and flow cytometry.
This award reflects NSF’s statutory mission and has been deemed worthy of support through evaluation using the Foundation’s intellectual merit and broader impacts review criteria.