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Innovative drug research targeting IgD and IgDR signaling for the regulation of T cell activity
Author(s) -
Wei Wei,
Wu Yujing
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.670.2
Subject(s) - immunoglobulin d , jurkat cells , t cell , biology , microbiology and biotechnology , signal transduction , immunology , immune system , antibody , cancer research , b cell
Immunoglobulin D (IgD), which remains a rather enigmatic player in the immune system, can be expressed as membrane IgD (mIgD) representing one of B cell receptors with an attached signaling machinery or can be secreted as an antibody (sIgD). sIgD has been found to be over‐expressed in several diseases, such as IgD myeloma, leukemia, tuberculosis, hyper IgD syndromes and autoimmune diseases. In addition, the IgD receptor (IgDR), which is firstly detected on CD4 + T cells, can activate the downstream signal transduction when binding to sIgD. Through quantitative immunofluorescence techniques, our group proved the existence of IgDR on T cells, B cells, fibroblast‐like synoviocytes (FLSs) and T‐cell acute lymphoblastic leukemia (T‐ALL) cell lines (Jurkat and MOLT‐4 cell lines). In patients with rheumatoid arthritis (RA), the levels of sIgD, mIgD and IgDR were higher than those in healthy controls. IgD could promote the proliferation and inhibit the apoptosis of CD4 + T cells, Jurkat and MOLT‐4 cell lines. More interestingly, The T‐ALL cell lines and CD4 + T cells from RA patients were more sensitive to IgD than CD4 + T cells from healthy controls. Excessive IgD was shown to bind to IgDR on CD4 + T cells in a concentration‐dependent manner and stimulate the activation and proliferation of these cells by enhancing phosphorylation of the activating tyrosine residue of Lck (Tyr394) and mTORC2/Akt/EGR1 pathway. The extremely important role of Lck and mTORC2/Akt/EGR1 pathway in CD4 + and T‐ALL T cells indicates the possible roles of excessive IgD in the pathogenesis of T cell activation, and further suggesting that IgD/IgDR may be a novel therapeutic target for treatment of T cell related diseases. Blocking the binding between IgD and IgDR may become a new strategy in the treatment of autoimmune diseases and hematological diseases. Targeting IgD and IgDR, our group firstly synthesized a fusion protein called IgD‐Fc‐Ig through connecting IgD‐Fc and IgG‐Fc domains, and this fusion protein aims to competitively inhibit the binding of IgD and IgDR. In vitro study, IgD‐Fc‐Ig per se did not show a significant effect on the proliferation of CD4 + T cells, Jurkat and MOLT‐4 cell lines but specifically inhibited the IgD‐induced pro‐proliferation and anti‐apoptosis effect via IgD/IgDR/mTORC2/Akt/EGR1 pathway. In the peripheral blood from RA patients, IgD‐Fc‐Ig could clearly down‐regulate IgD‐induced proliferation and activation of T cells, and restore IgD‐induced imbalance of Th17/Treg cell subsets. In collagen‐induced arthritis mouse, IgD‐Fc‐Ig treatment significantly reduced the severity of established arthritis and histopathological changes. IgD‐Fc‐Ig could also attenuate the related clinical manifestation due to its inhibitory effect on T cell activation and restore Th17/Treg imbalance. With a particular emphasis on the novel T cell‐targeted therapeutic strategies, our work highlights the immunologic features of IgD/IgDR and a novel direction of discovery and development of new drugs for the treatment of T cell related diseases. Support or Funding Information This research was supported by the National Natural Science Foundation of China (No. 81330081; 81673444; 81603121). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .