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T cells as therapeutic targets in SLE

Abstract

T cells contribute to the initiation and perpetuation of autoimmunity in systemic lupus erythematosus (SLE), and seem to be directly involved in the development of related organ pathology. Defects associated with CD8+ and T-regulatory (TREG) cell function manifest in parallel with the expanded CD3+CD4CD8 T cell lineage. The cytokine expression pattern is uniquely characterized by decreased expression of interleukin (IL)-2 and increased production of IL-17 and related cytokines. Therapeutic approaches that limit the cognate interaction between T cells and B cells, prevent inappropriate tissue homing and restore TREG cell function and the normal cytokine milieu have been entertained. Biochemical characterization of SLE T cells has revealed distinct early and late signaling aberrations, and has enabled the identification of novel molecular targets that can be corrected with small molecules, and biomarkers that may foretell disease activity and predict organ damage.

Key Points

  • Lipid raft clustering and a 'rewired' T-cell receptor lead to enhanced early signaling events in T cells from patients with systemic lupus erythematosus (SLE)

  • Signaling aberrations cause altered gene transcription and produce a unique T-cell phenotype in SLE

  • Increased numbers of CD3+CD4CD8 T cells and interleukin (IL)-17-producing T cells, along with limited numbers of regulatory T cells, facilitate inflammation and perpetuation of autoimmunity in SLE

  • Promising therapeutic targets include the interruption of T cell–B cell cognate interactions, restoration of IL-2 production, deletion of IL-17-producing T cells, and limitation of tissue infiltration by T cells

  • Restoration of abnormally expressed signaling molecules results in the correction of effector T-cell function in vitro and may prove to be an effective and novel therapeutic approach

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Figure 1: Distinct biochemical abnormalities explain the unique phenotype of SLE T cells.
Figure 2: In vivo T-cell activation increases CD44 adhesion capacity and T-cell migration.
Figure 3: Differentiation of T-cell subsets is biased in patients with SLE.

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Correspondence to George C. Tsokos.

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Crispín, J., Kyttaris, V., Terhorst, C. et al. T cells as therapeutic targets in SLE. Nat Rev Rheumatol 6, 317–325 (2010). https://doi.org/10.1038/nrrheum.2010.60

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