DC-HIL is a negative regulator of T lymphocyte activation

Abstract

IntroductionT-cell activation is dependent on signals delivered by antigenpresenting cells (APCs) to the antigen (Ag)-specific T-cell receptor (TCR) and accessory receptors on T cells. 1 The principal stimulatory accessory signal is transmitted by B7-1 (CD80) or B7-2 (CD86) on APCs to the CD28 receptor on T cells. 2 Interestingly, engagement of the same B7-1 or B7-2 ligand to CTLA-4 (CD152) on T cells markedly attenuates T-cell responses. 3,4 The importance of CTLA-4 as an inhibitory regulator of T-cell activation is illustrated by death of CTLA-4-deficient mice within 4 weeks of birth because of massive lymphocytic infiltration destroying critical organs. 5 More recently, other inhibitory regulators of T-cell activation were identified, including PD-L1 (B7-H1) and PD-L2 (B7-DC) on APCs and PD-1 on T cells, 6 BTLA on B cells and T helper 1 (Th1) effector cells and its ligand (herpes virus entry mediator) on T cells, 7,8 and Tim-3 on APCs and Th1 effector cells and Tim-3 ligand on CD4 ϩ T cells. [9][10][11] The T-cell ligands possess a single immunoglobulin (Ig)-like variable (IgV) domain, and the APC receptors contain both IgV and Ig constant (IgC) domains. 12 Interactions between ligand-receptor pairs are mediated predominantly by residues of Ig-like domains. 12 Because of their structural and functional similarities to B7 molecules, these ligands/receptors are considered members of the B7 receptor superfamily. 12 Ligation of PD-1 on T cells leads to inhibited T-cell responses that can be rescued by exogenous IL-2 or CD28 costimulation, [13][14][15] although one report showed that binding of PD-L1 (B7-H1) to PD-1 stimulated T-cell proliferation and IL-10 secretion. [16][17][18] PD-1 deficiency leads to exaggerated autoimmunity since PD-1 knockout mice develop splenomegaly, increased numbers of B and myeloid cells, increased serum IgG and IgA, and a lupus erythematosuslike disease with age. 19,20 These mice are also markedly susceptible to Ag-induced experimental autoimmune encephalomyelitis (EAE). 19,20 BTLA knockout mice do not exhibit developmental Tor B-cell defects, but their lymphocytes have heightened responses to anti-CD3 antibody (Ab) and to anti-IgM Ab; 8 these mice are also prone to developing EAE. 8 In the case of the Tim-3 pathway, its blockade by monoclonal Ab (mAb), Fc-fused soluble receptor, or gene disruption leads to exacerbated Th1-mediated autoimmune diabetes mellitus in nonobese diabetic (NOD) mice. 10,11 T-cell expression of PD-1, BTLA, or Tim-3 resembles CTLA-4 in that it is not constitutive, but is induced by activation. 21 Moreover, the costimulation delivered by each appears to be mediated through the TCR. 12 By contrast, expression of PD-1, BTLA, Tim-3, or their ligands differ from CTLA-4 in that it is not restricted to T cells, but is expressed more widely to include B cells and APCs. Indeed, some of these ligands (PD-L1 and PD-L2) are also expressed in nonlymphoid tissues. 12 Such broad expression profiles suggest that these molecules can modulate immune responses in secondary lympho...

Binding of DC-HIL to Dermatophytic Fungi Induces Tyrosine Phosphorylation and Potentiates Antigen Presenting Cell Function

“…We also found DC-HIL to deliver a potent inhibitory signal to T cells, in an Ag-independent manner, by binding a heparin/heparan-like saccharide of syndecan-4 (SD-4) on activated T cells (19,20). These findings led us to hypothesize that DC-HIL binds microbial pathogens in a similar manner.…”

“…Fc-fused proteins (DC-HIL-Fc, SD-4-Fc, Dectin-2-Fc, and Fc alone) were produced in COS-1 cells and purified as described previously (15,19).…”

Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells

“…Osteoactivin (DC-HIL) impairs APC function, which might be one explanation for the observed IL-10 effect. 12,34 To further analyze the underlying gene-expression regulatory mechanisms of our previous findings, we performed a semiquantitative reverse transcription-PCR (RT-PCR) analysis to detect mRNA expression of MyD88, IRAK1, TRAF6 and mTOR in APCs generated as above.…”

Expression of Gpnmb in NK Cell Development from Hematopoietic Stem Cells

“…These results show that pNK cell interacts with stromal cell, but not with pNK cell itself. It has been reported that Gpnmb binds to heparin heparan sulfate proteoglycan (12). In addition, one of the binding partner of Gpnmb is syndecan4 (SD4) on activated T cell which functions as a negative regulator on T cell activation, although SD4 on B cell did not bind to Gpnmb (12,13).…”

“…It has been reported that Gpnmb binds to heparin heparan sulfate proteoglycan (12). In addition, one of the binding partner of Gpnmb is syndecan4 (SD4) on activated T cell which functions as a negative regulator on T cell activation, although SD4 on B cell did not bind to Gpnmb (12,13). Thus, we determined the expression of SD4 and other SD family in OP9 cells to determine a candidate which enables to bind Gpnmb on cell surface (Fig.…”