Systemic lupus erythematosus (SLE, lupus) is characterized by the generation of pathogenic autoantibodies that promote tissue injury, including in the kidney. Pathogenic autoantibodies in lupus undergo affinity maturation and immunoglobulin (Ig) isotype switching in germinal centers (GCs) within secondary lymphoid organs (SLOs), a site of CD4+ T cell-dependent (TD) B cell maturation. Yet, the specific subsets of effector CD4+ T cells that promote auto-reactive B development, and the regulation of these cells, are not well defined. T follicular helper (Tfh) cells comprise a subset of CD4+ T helper (Th cells, phenotypically and functionally distinct from other Th cells, such as the classical the Th1, Th2 and Th17 subsets. They reside in B cell follicles and GCs and are essential for B cell maturation and (auto) antibody production. Tfh cells express proteins critical for their development and GC maturation. They also secrete the canonical cytokine interleukin (IL)-21 that is necessary for GC B cell development, as well as the classical Th1 and Th2 cytokines IFN- and IL-4, appropriate to pathogen challenge, and that are also necessary for B cell maturation as well as Ig isotype switch. Unlike the classical CD4+ Th1, Th2, and Th17 cell subsets, the mechanism of cytokine production by Tfh cells is unclear. I have used model systems to explore Tfh-cell cytokine production and its role in B cell maturation, with the long-term goal to investigate these events in pathogenic autoantibody production in SLE. I have demonstrated in work submitted for publication that Tfh cells following model (viral) infection secrete both IL-21 and IFN-? as do classical Th1 cells, and as also occurs in SLE. My findings underscore the complexity of the genetic regulation of cytokine production by CD4+ T cells following pathogen challenge and, importantly, in SLE. Inhibition of IFN-? and IL-21 is beneficial in murine lupus with these cytokines as therapeutic targets in SLE; however, their contribution to disease is not fully understood. I hypothesize that the factor(s) defining Tfh- cell cytokines compared to Th1 cells will have consequences in lupus, and may represent novel therapeutic targets. Accordingly, I will dissect the factors that regulate these responses in a viral infection model and in spontaneous lupus, utilizing novel genetically modified cytokine reporter mice that I have created and/or bred. I will use these tools to explore the interplay of transcriptional regulation, dynamic chromatin architecture, regulatory protein binding, and genomic organization in cytokine production in Th1 and Tfh cells following viral challenge (a tractable system) and in lupus (a more complex model), using novel genomics approaches combined with fundamental cellular immunology experiments. These tools will bolster my research skills in the setting of this career development award, and will enable me to identify the common classes of regulatory elements in both cytokine genes. Ultimately, this work should help me distinguish pathogenic and nonpathogenic effector T cells, aiding therapeutic design, and serve to launch my independent research career.
Molecules that are necessary for T lymphocyte effector function are critical for end-organ injury in systemic lupus erythematosus. Their identification and characterization will provide insight into therapeutic targets in disease.
| 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: |
| Weinstein, Jason S; Herman, Edward I; Lainez, Begoña et al. (2016) TFH cells progressively differentiate to regulate the germinal center response. Nat Immunol 17:1197-1205 |
