Current Research and Scholarly Interests
Dr. Jones' research has focused on genetic, molecular, and cellular mechanisms that regulate innate and adaptive immune responses. As immune responses can be harmful, they are highly regulated in their occurrence, magnitude, and duration. Her current work focuses on innate immune and inflammatory responses, triggered by conserved microbial components. Her research group discovered and is characterizing a novel mechanism that regulates innate responses of mammalian macrophages, dendritic cells, and other cells to microbial pathogens, resulting in generation of anti-microbial responses and production of cytokines and other proteins that contribute to innate, inflammatory, and adaptive immune responses. Dr. Jones' group discovered that the signaling pathways activated by the binding of microbial components to Toll-like receptors (TLR), leading to activation of the transcription factor NF-κB as well as MAPK pathways, is negatively-regulated by the protein phosphatase calcineurin. This inhibitory role of calcineurin, which helps to keep signaling downstream of TLR off in resting macrophages and other cells, is opposite to calcineurin's activating role in T and B lymphocytes following activation by antigen. Reflecting calcineurin's inhibitory role in macrophages, the signaling pathway downstream of TLR is activated by calcineurin inhibitors, such as cyclosporine A and FK506, that have long been used as immunosuppressants to block undesired T cell immune responses, such as those mediating organ transplant rejection.
To understand the physiological role of calcineurin in regulating innate immune responses in vivo, the Jones lab has explored the effect of inhibiting calcineurin in mice, using two experimental models. In the first model, mice received multiple injections of the calcineurin inhibitor FK506. In the second model, transgenic mice were created using the Cre-lox system that are deficient in the expression of calcineurin in myeloid cells. In both models mice were tested to see whether the resulting reduction in calcineurin activity led the activation of innate responses or alternatively, as has been observed with multiple exposures to microbial components such as bacterial lipopolysaccharide (LPS), to de-sensitization (a reduction in responsiveness referred to as LPS tolerance). In both models of reduced calcineurin activity, mice did not show upregulation of innate immune responses. In contrast, macrophages from these mice showed reduced responses to innate stimuli in vitro, and when challenged with a lethal dose of LPS (a model for septic shock) these mice showed partial protection. Thus, chronic inhibition of calcineurin activity leads to the induction of negative feedback pathways that limit the potential harmful effects of innate immune and inflammatory responses. These findings suggest that people chronically-treated with calcineurin inhibitor immunosuppressants, such as organ transplant recipients, may be suppressed in their innate as well as adaptive immune responses, perhaps contributing to the well-known increase in their susceptibility to infection.