Influenza-Specific T Cell Memory: Influenza of Obesity, Weight Loss, Weight Gain

Obesity is a global epidemic, with 10% of men and 14% of women obese worldwide. Obesity is a known risk factor for increased complications and death from infection with influenza virus, and impairs the T cell response to both influenza infection and vaccination. As obesity is primarily a metabolic disorder, and immune cell function is dictated by metabolism of the immune cell, the effect of obesity on memory T cell metabolism following a secondary influenza infection was investigated. This dissertation addressed whether the metabolic environment at the time of memory T cell generation or at the time of re-challenge would influence T cell metabolism and function. C57BL/6J high fat diet-induced obese mice were infected with X-31 influenza virus to generate memory T cells, then switched to a low-fat diet to induce weight loss. Following weight loss and normalized fasting glucose levels, mice were re-infected with influenza Puerto Rico/8/34 (PR8) to activate the memory T cells in a newly generated lean state. Conversely, lean mice were infected with X-31 to generate memory T cells followed by a diet switch to a high fat diet to induce obesity. Following weight gain and elevated fasting glucose levels, mice were re-exposed to PR8. Compared with mice that were always lean, mice that were obese for both primary and secondary influenza infections had impaired T cell metabolism and function. Mice that lost weight maintained a metabolic phenotype that paralleled the always obese metabolic phenotype along with dysregulated frequencies of central memory, effector memory, and tissue resident memory T cell populations and decreased function of influenza-specific memory T cell subsets. Mice that had gained weight, and were previously lean, maintained a metabolic profile similar to the mice that were always lean, although also had T cell subset alterations and diminished function. Altogether, this data demonstrates that metabolic environment present at the time of memory T cell generation and at time of secondary immune challenge both impact T cell function. For the first time, obesity has been shown to alter T cell metabolism, and we demonstrate that weight loss will not restore T cell metabolism or function.Doctor of Philosoph