Ectopic B-helper CD4+ T cells: Pathogenic CD4+ T cells regulating B-cell differentiation in autoimmunity: not exactly Tfh cells

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T follicular helper (Tfh) cells are typically defined by the expression of CXCR5, PD-1 and BCL-6, and their ability to promote the differentiation of B cells into antibody (Ab)-producing plasma cells.1,2 In a recent article in Nature, Brenner and colleagues described a putative pathogenic population of B-helper CD4+ T cells in tissues from patients with rheumatoid arthritis (RA).3 Curiously, while these cells expressed high levels of PD-1 and promoted B-cell differentiation, they lacked CXCR5 and BCL-6, suggesting they represent a novel subset of effector CD4+ T cells.
A fundamental function of B cells is to produce Abs that recognize and bind specific antigens on microbes, resulting in the neutralization and/or eradication of infectious pathogens.4 B cells usually require inputs from various cell types to ensure they produce the most appropriate class of Abs. The key cell type involved in this process is the Tfh cell, a subset of CD4+ T cells specialized to provide ‘help’ to B cells.1,2 Cardinal features of Tfh cells include expression of the B-cell zone homing chemokine receptor CXCR5, the transcriptional repressor BCL-6, the cytokine interleukin (IL)-21, the chemokine CXCL13 and a suite of surface molecules—CD40L, ICOS, SLAM receptors, PD-1—involved in T-cell/B-cell interactions.1,2 Critically, Tfh cells localize with B cells in follicles and germinal centers in secondary lymphoid tissues and promote the differentiation of activated B cells into memory cells and Ab-secreting plasma cells.1,2 It is this ability of B cells to generate memory and plasma cells that underlies long-lived serological memory following pathogen infection, and the success of most currently available vaccines that protect the host against infection for extended periods of time, and in some instances a life time.4
However, not all Abs produced by B cells are good—in fact, in the setting of autoimmunity, autoreactive B cells are pathogenic, producing Abs that result in severe tissue damage and ultimately organ failure.5 Akin to responses against non-self antigens, the production of autoAbs by B cells can be driven by Tfh cells.5 Indeed, many studies have reported increased proportions of circulating Tfh-like cells (usually defined as CXCR5+PD-1hi or CXCR5+ICOShi CD4+ T cells) in the peripheral blood of patients with a broad range of autoimmune diseases often associated with production of autoAbs, such as systemic lupus erythematosus (SLE), Sjogren’s syndrome, RA and diabetes.2,5-8 Remarkably, the proportions of circulating Tfh-like cells in these immunopathologies often correlates with levels of autoAbs or other readouts of disease, and therapeutic interventions that alleviate disease severity also reduced Tfh-like cells.2,5-8 Collectively, these studies have defined Tfh cells—along with their partner B cells—as being drivers of autoimmunity in humans, and thus represent targets for potential therapies.
A limitation of many studies performed to date that have investigated the potential role of Tfh cells in human autoimmunity is that analysis has largely been performed on blood cells—when clearly the ‘action’ in these conditions occurs in affected tissues. Thus, a strength of the study by Rao et al.3 is their access to inflamed tissues and peripheral blood from individuals with RA, coupled with the multidimensional analysis of cells in these sites. Synovial fluid and synovial tissue from patients with seropositive, but not seronegative, RA were found to be enriched for a population of memory CD4+ T cells expressing high levels of PD-1, MHC class II and ICOS. Transcriptional assessment of these PD-1hi CD4+ T cells revealed them to contain higher levels of messenger RNA encoding IL-21, CXCL13, MAF, SAP, BATF, OX2 (CD200) and BTLA than PD-1− CD4+ T cells present in the same sites.
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