CD4 T cell help is crucial for B cell production of antibodies that occurs in germinal centers (GCs) of secondary lymphoid organs (SLOs), a site of immunoglobulin (Ig) affinity maturation and isotype switching. In GCs, T follicular helper (Tfh) cells provide B cells with survival and differentiation signals, including CD40 ligand (CD40), programmed death receptor-1 (PD-1), and IL-21, essential for B cell selection with maturation into memory B cells and long-lived antibody-secreting (plasma) cells. Tfh cells can be distinguished from other CD4 effector cells;e.g., the Th1, Th2, and Th17 subsets (among others), by their GC location and function as B cell helpers. Tfh cells are critical for B cell hel in both normal and autoimmune responses;yet, the development and function of these cells, compared to other CD4 T effector cell subsets, is less clear. To address this issue, we have devised an approach to selectively mark and/or delete these cells chronologically during normal and aberrant immune responses. To accomplish this goal, we will take advantage of our recent observation that ectodin, an inhibitor of bone morphogenetic proteins (BMPs), is selectively expressed by Tfh cells among other immune cells. Here we propose the development of an in vivo system to specifically target and manipulate Tfh cells using the ectodin promoter. We propose to make a tamoxifen-inducible-Cre mouse in which Cre, fused with the estrogen receptor ERT2, will be expressed downstream of the ectodin gene (Sostdc1);the targeting construct has already been made, sequence verified, purified, and micro-injected into embryonic stem cells. When crossed with the appropriate reporter strain (e.g., Rosa-26-YFP), deleter strain (R-DTA mouse) or with strain(s) that expresses a target gene flanked by two loxP sites, it will allow us to specifically track or ablate Tfh cells, or engender a Tfh- specific deletion of genes a desired time points during an immune or autoimmune response;the latter will be accomplished by crossing our inducible Cre mouse with appropriate lupus-prone strains. Currently there is no way to specifically target and analyze the role of Tfh cells in immune responses;thus, we believe our approach of creating an inducible, Tfh cell-specific Cre mouse will open up opportunities to study different aspects of Tfh biology.

Public Health Relevance

Subset of T cells, follicular helper T cells, is necessary for helping B lymphocytes produce antibodies and autoantibodies in normal and autoimmune responses. 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. The results of the proposed studies should help address these issues, and advance knowledge of how autoimmune responses develop in humans.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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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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Weinstein, Jason S; Herman, Edward I; Lainez, BegoƱa et al. (2016) TFH cells progressively differentiate to regulate the germinal center response. Nat Immunol 17:1197-1205
Laidlaw, Brian J; Craft, Joseph E; Kaech, Susan M (2016) The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol 16:102-11
Ray, John P; Staron, Matthew M; Shyer, Justin A et al. (2015) The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells. Immunity 43:690-702
Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A et al. (2015) Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol 16:871-9
Ray, John P; Marshall, Heather D; Laidlaw, Brian J et al. (2014) Transcription factor STAT3 and type I interferons are corepressive insulators for differentiation of follicular helper and T helper 1 cells. Immunity 40:367-77
Weinstein, Jason S; Bertino, Sarah A; Hernandez, Sairy G et al. (2014) B cells in T follicular helper cell development and function: separable roles in delivery of ICOS ligand and antigen. J Immunol 192:3166-79
Laidlaw, Brian J; Zhang, Nianzhi; Marshall, Heather D et al. (2014) CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41:633-45
Shulman, Ziv; Gitlin, Alexander D; Weinstein, Jason S et al. (2014) Dynamic signaling by T follicular helper cells during germinal center B cell selection. Science 345:1058-62
Bertino, Sarah A; Craft, Joe (2013) Roquin paralogs add a new dimension to ICOS regulation. Immunity 38:624-6
Look, Michael; Stern, Eric; Wang, Qin A et al. (2013) Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice. J Clin Invest 123:1741-9

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