NFAT proteins and immune cells

Role of NFAT transcription factors in the regulation of gene expression in immune cells. Gene expression is the final result of complex signaling networks that communicate environmental changes to the nucleus of the cell. Once the sequencing of the human genome was completed, a growing area of investigation is now concentrated in studying specificity, timing, and regulation of gene expression. Our main interest is to identify points of control in immune responses at the level of gene expression regulation. Rel transcription factors (NF-κB and NFAT proteins) play central roles in immunity and are prominent targets of immunosuppressive and anti-inflammatory approaches. We have focused our recent work on NFAT5, a distinct Rel-like protein with hybrid features between NF-κB and the calcineurin-regulated NFATc, to whose characterization our group has contributed significantly. We have generated NFAT5-deficient mouse models to elucidate specific roles for NFAT5 in the immune system, identified pathways connecting cell growth-regulatory mechanisms with stress adaptation responses, and uncovered an unsuspected role for NFAT5 in anti-pathogen defenses. Understanding the relative contribution of NFAT5 versus other Rel (NF-kappaB and NFAT) proteins during immune responses, and also in other systems, is particularly relevant given that NFAT5 is activated by stimuli that both do (stimulation through the T lymphocyte receptor) and do not (hypertonicity) elicit the activation of NF-kappaB or conventional NFAT proteins. Moreover, the mechanism of activation of NFAT5 indicates that the analysis of its regulation and function could provide clues for better understanding both the normal function of the immune system and its pathological alterations.

Influence of stress adaptation responses in immune cell functions. Dynamic regulation of gene expression allows cellular adaptation to diverse stimuli. The coordinated action of intracellular signaling cascades and transcription factors ensures that cells are able to accurately interpret a huge diversity of inputs, including stress conditions. Adaptive stress responses allow cells to survive microenvironment disturbances until homeostasis is reestablished. Importantly, stress is not an occasional threat, but in variable forms it is intrinsic to life and integrated in the flow of information that cells exchange with their environment. This connection is still poorly understood, but is particularly relevant in the immune system, composed by mobile cells that function in a variety of anatomical niches where they can be exposed to diverse stress sources, but have to maintain adequate responsiveness to relevant signals from tissues and threats such as pathogens. Our current work focuses on understanding how immune cells interpret specific stress signals in different growth and differentiation contexts to modify their functional capabilities in an organism.