) Systemic lupus erythematosus (SLE, lupus) is characterized by the generation of autoantibodies that promote tissue injury. Follicular B helper T (Tfh) cells, phenotypically and functionally distinct from other T-helper (Th) cell subsets, reside in B-cell follicles and germinal centers (GCs) of secondary lymphoid organs, where they are essential for B-cell proliferation and survival, immunoglobulin (Ig) affinity selection, and development of memory B and long-lived plasma cells. The regulation of Tfh cells, and how in turn these cells promote autoreactive B cell responses, are critical to understanding the generation of pathogenic autoantibodies in SLE, and ultimately, to determining therapeutic intervention. Tfh cells, and the GC B cells they help, persist in lupus with induction of autoreactive memory B cells and autoantibody-producing plasma cells, by contrast to their appropriate waning following immunization or acute infection. The chronicity of autoreactive Tfh- and B-cell responses in lupus, integral to the disease phenotype, is not well understood. To address this phenomenon, we chronologically analyzed the phenotype and transcriptional profiles of Tfh cells in lupus. Tfh-cell cytokine production was aberrantly regulatd in murine lupus, with persistent co-production of the canonical Tfh-cell cytokine IL-21, alongside interferon-? (IFN-?). We also found simultaneous IL-21 and IFN-? double-producing Tfh cells in in the kidneys of lupus-prone mice, and in the blood of SLE patients. Among the transcriptional changes we observed in lupus Tfh cells was development of a gene signature associated with signal transducer and activator of transcription (STAT) 4, a risk allele strongly associated with the development of SLE that correlated with the maintenance and persistence of the aberrant cytokine producing Tfh cells. By contrast to immunization or acute infection in which Th-cell cytokine production resolves physiologically, in human and murine lupus it persists pathologically, with STAT4 signaling critical for maintenance. We hypothesize that the inflammatory milieu of lupus leads to STAT4-mediated transcriptional changes in Tfh cells causing them to acquire an aberrant pattern of cytokine production, which then promotes pathologic B-cell maturation with autoantibody production. Our plan in this competitive renewal application is to investigate this hypothesis, addressing how the evolving, aberrant Tfh-cell phenotype promotes autoreactive B cell maturation; assessing STAT4-mediated genomic regulation of Tfh cells in lupus; and examining the factors that promote STAT4 signaling in an effort to determine the drivers of the aberrant Tfh-cell phenotype in lupus. We will answer these questions using murine model systems, and to the extent possible, in parallel with experiments using cells from patients with SLE.

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AR040072-30
Application #
9912725
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
1990-08-31
Project End
2021-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
30
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Weinstein, Jason S; Laidlaw, Brian J; Lu, Yisi et al. (2018) STAT4 and T-bet control follicular helper T cell development in viral infections. J Exp Med 215:337-355
Laidlaw, Brian J; Lu, Yisi; Amezquita, Robert A et al. (2017) Interleukin-10 from CD4+ follicular regulatory T cells promotes the germinal center response. Sci Immunol 2:
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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
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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

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