Systemic lupus erythematosus in 2015: Cellular and metabolic requirements of effector T cells


lar helper T (TFH) cells and the contribution of T cells to tissue damage are topics that have received considerable interest within the field of lupus research. A number of stellar findings reported in 2015 draw attention to the ability of myeloid antigen-presenting cells (APCs) to stimulate the differentiation of TFH cells and sustain effector T cells at sites of inflammation. These findings also demonstrate that activated T cells in lupus use both aerobic glycolysis and oxidative phosphorylation to meet their energy requirements (FIG. 1). TFH cells, a subset of CD4 + T cells, have been credited with having a major role in the expression of autoimmunity because they provide expert help to B cells to form germinal centres, class-switch and produce high-affinity antibodies. TFH cells produce IL-21 and express inducible T-cell co-stimulator (ICOS); the successful blockade of either of these inflammatory mediators limits autoimmunity and lupus-like disease. Furthermore, TFH cells seem to have an additional role in human systemic lupus erythematosus (SLE): these cells are expanded in the peripheral blood of patients with SLE (more so when the disease is active) and are present in the kidneys of patients with lupus nephritis. Therefore, TFH cells are plausible treatment targets1. Jacquemin et al.2 presented evidence that the OX40 ligand (OX40L)–OX40 axis is important in the generation of TFH cells in both young patients and adults with SLE. OX40L (also known as TNF ligand superfamily member 4) was found to be expressed on the surface of myeloid (CD11c+) APCs in inflamed to produce immunoglobulin. Engagement of the T-cell receptor in SLE T cells is known to generate a strong signal1, and this signal seems to be important in the generation of TFH cells. Jacquenin et al.2 showed that engagement of OX40 on TFH cells enhances this signal further. Lastly, the study showed that ribonucleoprotein (RNP)–anti-RNP immune complexes, which are abundant in patients with SLE, stimulate myeloid APCs to express OX40L through Toll-like receptor 7 activation. So, the OX40L–OX40 axis seems to be part of a linear pathogenic course: immune complexes induce myeloid APCs to express OX40L that promotes the differentiation of TFH cells, which lead to antibody production and homing of T cells to inflamed tissues. Given the strong clinical correlations obtained in cross-sectional patient samples, prospective studies to determine whether OX40L+ APCs precede disease activity, or whether they become part of a grossly dysregulated immune system, are obviously required. In mice, the activity of TFH cells is regulated by follicular regulatory T (TFR) cells 3. Although such cells are thought to operate in humans as well, it is not known whether the activity of TFH cells is simply boosted by the kidneys from patients with lupus nephritis and in the peripheral blood of patients with active SLE. By contrast, peripheral blood B cells expressed minimal, if any, OX40L on their surface. Soluble OX40L, in the presence of canonical T-cell stimulation in vitro, promoted the expression of TFH cell signature molecules including CXC-chemokine receptor 5 (CXCR5), B-cell lymphoma 6 protein (BCL-6) and IL-21. Interestingly, the generated TFH cells could support autologous B cells S Y S T E M I C L U P U S E RY T H E M ATO S U S I N 2 0 1 5

DOI: 10.1038/nrrheum.2015.178

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@article{Tsokos2016SystemicLE, title={Systemic lupus erythematosus in 2015: Cellular and metabolic requirements of effector T cells}, author={George C Tsokos}, journal={Nature Reviews Rheumatology}, year={2016}, volume={12}, pages={74-76} }