Background/Purpose:  IL-7 is a potent T cell activating cytokine that has been shown to cause proliferation, survival and differentiation of T cells as well as T cell-dependent activation of myeloid cells in numerous conditions. In inflamed tissues of patients with several autoimmune diseases (RA, pSS, psoriasis) increased IL-7 production by tissue cells and immune cells has been documented. Although reduced serum immunoglobulin levels in IL-7R-deficient individuals suggested that IL-7 might play a role in activation of mature human B cells, direct evidence for this is lacking. Previously, it has been demonstrated that EBV, one of the suggested triggers of pSS, induces TLR7-dependent B cell activation and that EBV-transformed B cells express significant levels of the IL-7R as well as IL-7. Furthermore, we have shown that both intracellular IL-7R and IL-7 expression is up regulated in vitro upon TLR7 triggering of B cells. Our purpose was to investigate the potential synergy of IL-7-driven T cell-dependent and TLR7-mediated B cell activation and to assess the additive effects of monocyte/macrophages in this respect.

Methods:  Isolated CD19 B cells and CD4 T cells from HC (n=7) were co-cultured (1:1) with and without IL-7, TLR7 agonist (TLR7A, Gardiquimod) or the combination of IL-7/TLR7A with and without CD14 monocytes/macrophages (T/B/mono; 1:1:0,1). Proliferation of T and B cells was measured using 3H-thymidine incorporation and by Ki67 expression (FACS analysis). Activation marker (CD19, HLA-DR, CD25) expression was measured by FACS analysis. In addition, in culture supernatants cytokines (IFNg, IL-17A, IL-22, IL-6 and IL-10) and IgM and IgG were measured by Luminex and ELISA, respectively. 

Results: Exogenously added IL-7 did not activate B cells directly, in line with the absence of surface IL-7R. However, in the presence of T cells, IL-7 activated both T and B cells (Ki67+ CD4 cells from 1.1% to 14.4%, p<0.01 and Ki67+ B cells from 1.9% to 4.10.9%, p<0.05). TLR7A induced B cell activation, as measured by increased proliferation (%Ki67 from 1.2% to 9.3%) and up regulation of activation markers on B cells, which was facilitated in the presence of monocytes. TLR7-induced B cell activation in T/B or T/B/monocyte co-cultures was not associated with T cell activation. IL-7 added to TLR7A synergistically increased both B cell (TLR7A vs. IL-7/TLR7A; 9.3% vs. 33.4%) and T cell proliferation (IL-7 vs. IL-7/TLR7A; 0.8% vs. 29.2 %), which for B cells again was further increased by monocytes (TLR7A vs. IL-7/TLR7A; 30.2% vs. 63.0%)(all p<0.05). Similar results were observed for activation marker expression on B cells (CD19, HLA-DR CD25) and on T cells (HLA-DR, CD25). More important, IL-7 and TLR7, in the presence of monocytes, synergistically induced Th1/Th17/Th22 cytokine secretion and IgG production (all p<0.05)

Conclusion: IL-7 and TLR7 signaling synergistically activates T and B cells, which is markedly enhanced by the presence of monocytes/macrophages. Our results indicate that previously described increased local expression of IL-7 and TLR7 and increased numbers of macrophages in patients with pSS could contribute to enhanced lymphocyte activation and immunopathology in these patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-7-and-toll-like-receptor-7-synergistically-increase-th1th17th22-cytokine-secretion-and-activity-of-b-cells/