Abstract
In the ectopic lymphoid‐like structures present in chronic inflammatory conditions such as rheumatoid arthritis, a subset of human effector memory CD4+ T cells that lacks features of follicular helper T (Tfh) cells produces CXCL13. Here, we report that TGF‐β induces the differentiation of human CXCL13‐producing CD4+ T cells from naïve CD4+ T cells. The TGF‐β‐induced CXCL13‐producing CD4+ T cells do not express CXCR5, B‐cell lymphoma 6 (BCL6), and other Tfh‐cell markers. Furthermore, expression levels of CD25 (IL‐2Rα) in CXCL13‐producing CD4+ T cells are significantly lower than those in FoxP3+ in vitro induced Treg cells. Consistent with this, neutralization of IL‐2 and knockdown of STAT5 clearly upregulate CXCL13 production by CD4+ T cells, while downregulating the expression of FoxP3. Furthermore, overexpression of FoxP3 in naïve CD4+ T cells downregulates CXCL13 production, and knockdown of FoxP3 fails to inhibit the differentiation of CXCL13‐producing CD4+ T cells. As reported in rheumatoid arthritis, proinflammatory cytokines enhance secondary CXCL13 production from reactivated CXCL13‐producing CD4+ T cells. Our findings demonstrate that CXCL13‐producing CD4+ T cells lacking Tfh‐cell features differentiate via TGF‐β signaling but not via FoxP3, and exert their function in IL‐2‐limited but TGF‐β‐rich and proinflammatory cytokine‐rich inflammatory conditions.
Highlights
Ectopic lymphoid-like structures (ELSs), discrete clusters of T cells, B cells, macrophages, and dendritic cells (DCs) have been observed in inflamed sites of infections, tumors, and autoimmuneC 2015 The Authors
To explore the conditions that induce the generation of CXCL13-producing cells, we activated human blood CD4+ T cells with anti-CD3/CD28 antibodies under the conditions for differentiation of Th0, Th1, Th2, or Th17
CXCL13 is a chemokine that is crucial for the GC formation in secondary lymphoid organs [7], and ectopic expression of CXCL13 is sufficient for the generation of ELSs [6]
Summary
Ectopic lymphoid-like structures (ELSs), discrete clusters of T cells, B cells, macrophages, and dendritic cells (DCs) have been observed in inflamed sites of infections, tumors, and autoimmuneC 2015 The Authors. Ectopic lymphoid-like structures (ELSs), discrete clusters of T cells, B cells, macrophages, and dendritic cells (DCs) have been observed in inflamed sites of infections, tumors, and autoimmune. Cellular immune response diseases [1,2,3] These structures support several types of immune responses including antibody production, class switching, and affinity maturation, and the induction of effector functions, leading to protective immunity in infections, better prognosis in cancers, and autoantibody production or treatment-resistance in autoimmune diseases [1, 3,4,5]. Levels of chemokines including C-X-C motif chemokine 12 (CXCL12), CXCL13, C-C motif chemokine 19 (CCL19), and CCL21 are elevated in these inflamed tissues and are considered to regulate the cellular distribution and functional features of ELSs [1]. While follicular DCs are well known to contribute to the generation of GC in secondary lymphoid organs via CXCL13 production [7, 8], human CD4+ T cells have been noted to produce CXCL13 in ELSs [1, 3, 9,10,11,12]
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