T cells as therapeutic targets in SLE - PubMed (original) (raw)

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T cells as therapeutic targets in SLE

José C Crispín et al. Nat Rev Rheumatol. 2010 Jun.

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 (T(REG)) cell function manifest in parallel with the expanded CD3(+)CD4(-)CD8(-) 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 T(REG) 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.

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Figures

Figure 1

Figure 1

Distinct biochemical abnormalities explain the unique phenotype of SLE T cells. Decreased levels of CD3ζ and abnormal association of FcRγ with the CD3–TCR complex results in the ’rewiring’ of the TCR through Syk rather than ZAP-70. The resulting increase in intracellular calcium concentration causes an imbalance in transcription factor activation, particularly toward high nuclear migration of NFAT. High CaMK4 activity, along with abnormally elevated PP2A levels, alters the balance between CREB and CREM in favor of the latter, leading to decreased transcription of IL-2. Abbreviations: CaMK4, calcium/calmodulin-dependent protein kinase IV; CREB, cAMP response element binding protein; CREM, cAMP response element modulator; IL, interleukin; NFAT, nuclear factor of activated T cells; PP2A, protein phosphatase 2; SLE, systemic lupus erythematosus; Syk, spleen tyrosine kinase; ZAP-70, ζ-chain-associated protein kinase 70.

Figure 2

Figure 2

In vivo T-cell activation increases CD44 adhesion capacity and T-cell migration. T-cell stimulation by anti-CD3–TCR autoantibodies and/or autoantigens induces the activation of ROCK. ROCK phosphorylates ERM proteins, which then associate with CD44. The net effect is an increase in the adhesion and migration capacity of the T cell. Abbreviations: ERM proteins, ezrin, radixin and moesin proteins; ROCK, Rho kinase; TCR, T cell receptor.

Figure 3

Figure 3

Differentiation of T-cell subsets is biased in patients with SLE. Increased production of IL-6 by APCs, along with decreased IL-2 secretion by T cells, facilitates the differentiation of IL-17-producing cells whilst inhibiting the development of TREG cells. TFH cells, a CD4 subset specialized in providing help to B cells via expression of CD40L and IL-21 is also enhanced in SLE. These cells, along with elevated mononuclear IL-10 production, stimulate B cells to produce autoantibodies. Generation of proinflammatory DN (CD4−CD8−) T cells from CD8+ precursors is increased in patients with SLE, and CD8+ cytotoxic T-cell responses are diminished. Abbreviations: APC, antigen-presenting cell; CD40L, CD40 ligand; DN, double negative; IL, interleukin; SLE, systemic lupus erythematosus; TFH cell, follicular helper T cell; TH17 cell, type 17 helper T cell; TREG cell, regulatory T cell.

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