Immune cells called follicular helper T cells are enablers that allow B cells to produce autoantibodies (ANAs) that harm patients’ own tissues in lupus. A protein known as NFAT acts as a master switch to activate follicular T cells, turning the cells on and allowing them to function. We suspect that NFAT may work differently in follicular helper T cells in lupus, which could explain why B cells attack patients’ own tissues in the disease. To test our hypothesis, we will first analyze cells from healthy mice to determine how NFAT normally works. We will then test cells from mice and patients with lupus to see if and how NFAT functions changes in those with the disease. Drugs known as calcineurin inhibitors, now under study as treatments for kidney disease in lupus, inhibit NFAT and may prevent function of follicular helper T cells, although the precise mechanisms of how these drugs work are unclear. Our studies will test calcineurin inhibitors in mouse and human follicular helper T cells to determine whether they block the cells. The results of the proposed studies should help researchers better understand how T follicular cells may be improperly regulated in lupus and may point to new or improved therapies for lupus.

What this study means to people with lupus

“B cells damage patients’ own tissues, but they can’t launch their attacks without assistance from another type of immune cells called follicular helper T cells. We are trying to find out whether a certain protein allows these accomplice cells to behave differently in lupus and whether drugs under development will inhibit the function of the cells. A better understanding of how these partners operate can open new treatment avenues for lupus.”

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 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 found that NFAT operates in an AP-1 independent mode in Tfh cells activated under physiologic circumstances, 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 autoreactive B cell help and subsequent pathogenic autoantibody production. We will address our hypothesis using murine models and cells from lupus patients. Mice are excellent tools for the investigation of lupus, but the utility of such models is magnified when analyzed alongside 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 signaling is necessary and/or sufficient for their development and function, and identifying downstream effector pathways, with the goal to develop a comprehensive profile of NFAT signaling in Tfh cells, a comparator to our studies of such cells in lupus. In aim 2, we will interrogate NFAT signaling in dysregulated Tfh cells in murine lupus and investigate the molecular and cellular effects of calcineurin inhibition on disease. 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 define possible therapies.