PROJECT SUMMARY (ABSTRACT)
Systemic lupus erythematosus (SLE, lupus) is characterized by the generation of autoantibodies that promote
tissue injury. Follicular helper T (Tfh) cells in B-cell follicles and germinal centers (GCs) of secondary lymphoid
organs are necessary for B-cell proliferation and survival, immunoglobulin (Ig) affinity selection, and
development of memory B and long-lived plasma cells following vaccination and pathogen challenge.
Autoreactive Tfh cells and GC B cells develop and persist in SLE, with generation of autoreactive memory B
cells and autoantibody-producing plasma cells. The mechanism(s) of activation and maintenance of Tfh cells in
lupus, and how they in turn promote autoreactive B cell responses, are critical to understanding the generation
of pathogenic autoantibodies and subsequent tissue injury, and in determining therapeutic intervention.
The Nuclear Factor of Activated T cells (NFAT) family of transcription factors is ubiquitously activated upon T
cell receptor (TCR) signaling. NFAT is activated by the phosphatase calcineurin: in canonical NFAT signaling,
dephosphorylated NFAT translocates to the nucleus and cooperates with other transcription factors, such as
AP-1 family members, to activate gene transcription of cytokines, including IL-2, as well as of other soluble and
cell-surface effectors. We have determined that NFAT operates in an AP-1 independent mode in Tfh cells
activated upon viral infection of non-autoimmune mice, distinct from that of other T cell populations, a signaling
mode we believe essential to the unique function of Tfh cells in the GC environment. It is not known if the same
occurs in the abnormal, persistent GC response in lupus.
We hypothesize that AP-1 independent NFAT signaling is essential for development and function of Tfh cells,
and that understanding this unique mode of NFAT signaling will provide insight into the Tfh-cell function in
lupus with persistence of B cell help necessary for autoantibody production. We will address our hypothesis
using murine models and cells from lupus patients. Mouse models are excellent tools for studies of disease
pathogenesis; yet, their utility is magnified when analyzed alongside investigation of patients. We propose two
aims. In aim 1, we will interrogate NFAT signaling in Tfh cells in non-autoimmune mice, determining if AP-1
independent NFAT signaling is necessary and/or sufficient for Tfh cell development and function, and
identifying the downstream effector pathways of NFAT in Tfh cells, with the goal to develop a comprehensive
profile of NFAT signaling in Tfh cells. This information will serve as an essential comparator to our studies of
lupus Tfh cells in aim 2. In the latter, we will interrogate NFAT signaling in dysregulated Tfh cells in murine
lupus and investigate the molecular and cellular effects of calcineurin inhibition on disease initiation,
progression, and organ damage. We will then test the relevance of our findings using Tfh cells from patients
with SLE. This information will enable us to determine if Tfh-cell signaling pathways are altered in systemic
autoimmunity, and dissect possible avenues of therapeutic intervention in disease.