) 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.

Public Health Relevance

A subset of T cells, follicular B helper T cells, is necessary to provide help for B lymphocytes in their production of antibodies and autoantibodies in normal and autoimmune responses, respectively. Much remains to be learned about the biology of the former, including the requirements for their maturation and function, and how to interrupt their collaboration with B cells as a potential therapy for autoimmune diseases such as systemic lupus erythematosus (SLE or lupus). The results of the proposed studies should help address these issues, and advance knowledge of how lupus develops in humans.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Mancini, Marie
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Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
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