CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness

CD4+CD25+ regulatory T cells inhibit organ-specific autoimmune diseases induced by CD4+CD25−T cells and are potent suppressors of T cell activation in vitro. Their mechanism of suppression remains unknown, but most in vitro studies suggest that it is cell contact–dependent and cytokine independent. The role of TGF-β1 in CD4+CD25+ suppressor function remains unclear. While most studies have failed to reverse suppression with anti–transforming growth factor (TGF)-β1 in vitro, one recent study has reported that CD4+CD25+ T cells express cell surface TGF-β1 and that suppression can be completely abrogated by high concentrations of anti–TGF-β suggesting that cell-associated TGF-β1 was the primary effector of CD4+CD25+-mediated suppression. Here, we have reevaluated the role of TGF-β1 in CD4+CD25+-mediated suppression. Neutralization of TGF-β1 with either monoclonal antibody (mAb) or soluble TGF-βRII-Fc did not reverse in vitro suppression mediated by resting or activated CD4+CD25+ T cells. Responder T cells from Smad3−/− or dominant-negative TGF-β type RII transgenic (DNRIITg) mice, that are both unresponsive to TGF-β1–induced growth arrest, were as susceptible to CD4+CD25+-mediated suppression as T cells from wild-type mice. Furthermore, CD4+CD25+ T cells from neonatal TGF-β1−/− mice were as suppressive as CD4+CD25+ from TGF-β1+/+ mice. Collectively, these results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-β1

Transforming Growth Factor-β Production and Myeloid Cells Are an Effector Mechanism through Which CD1d-restricted T Cells Block Cytotoxic T Lymphocyte–mediated Tumor Immunosurveillance: Abrogation Prevents Tumor Recurrence

Our previous work demonstrated that cytotoxic T lymphocyte (CTL)-mediated tumor immunosurveillance of the 15-12RM tumor could be suppressed by a CD1d-restricted lymphocyte, most likely a natural killer (NK) T cell, which produces interleukin (IL)-13. Here we present evidence for the effector elements in this suppressive pathway. T cell–reconstituted recombination activating gene (RAG)2 knockout (KO) and RAG2/IL-4 receptor α double KO mice showed that inhibition of immunosurveillance requires IL-13 responsiveness by a non–T non–B cell. Such nonlymphoid splenocytes from tumor-bearing mice produced more transforming growth factor (TGF)-β, a potent inhibitor of CTL, ex vivo than such cells from naive mice, and this TGF-β production was dependent on the presence in vivo of both IL-13 and CD1d-restricted T cells. Ex vivo TGF-β production was also abrogated by depleting either CD11b+ or Gr-1+ cells from the nonlymphoid cells of tumor-bearing mice. Further, blocking TGF-β or depleting Gr-1+ cells in vivo prevented the tumor recurrence, implying that TGF-β made by a CD11b+ Gr-1+ myeloid cell, in an IL-13 and CD1d-restricted T cell–dependent mechanism, is necessary for down-regulation of tumor immunosurveillance. Identification of this stepwise regulation of immunosurveillance, involving CD1-restricted T cells, IL-13, myeloid cells, and TGF-β, explains previous observations on myeloid suppressor cells or TGF-β and provides insights for targeted approaches for cancer immunotherapy, including synergistic blockade of TGF-β and IL-13

Regulation of Tumor Immune Surveillance and Tumor Immune Subversion by TGF-β

Transforming growth factor-β (TGF-β) is a highly pleiotropic cytokine playing pivotal roles in immune regulation. TGF-β facilitates tumor cell survival and metastasis by targeting multiple cellular components. Focusing on its immunosuppressive functions, TGF-β antagonists have been employed for cancer treatment to enhance tumor immunity. TGF-β antagonists exert anti-tumor effects through #1 activating effector cells such as NK cells and cytotoxic CD8+ T cells (CTLs), #2 inhibiting regulatory/suppressor cell populations, #3 making tumor cells visible to immune cells, #4 inhibiting the production of tumor growth factors. This review focuses on the effect of TGF-β on T cells, which are differentiated into effector T cells or newly identified tumor-supporting T cells

Significance of antiprothrombin antibodies in patients with systemic lupus erythematosus: clinical evaluation of the antiprothrombin assay and the antiphosphatidylserine/prothrombin assay, and comparison with other antiphospholipid antibody assays

Antibodies against prothrombin are detected by enzyme immunoassays (EIA) in sera of patients with antiphospholipid syndrome (APS). However, there are two methods for antiprothrombin EIA; one that uses high binding plates (aPT-A), and another that utilizes phosphatidylserine bound plates (aPS/PT). We aimed to evaluate and compare aPT-A and aPS/PT in a clinical setting. We performed EIA for anti-PT, anti-PS/PT, IgG, and IgM anticardiolipin antibodies (aCL), and IgG β2-glycoprotein I-dependent aCL (aβ2GPI/CL) with serum samples from 139 systemic lupus erythematosus (SLE) patients (16 with history of at least one thrombotic episode) and 148 controls. We observed that: (1) although titers of anti-PT and anti-PS/PT were significantly related with each other (P < 0.0001, ρ = 0.548), titer of anti-PT and anti-PS/PT differed greatly in some samples; (2) odds ratio and 95% confidence interval for each assay was 3.556 (1.221–10.355) for aPT-A, 4.591 (1.555–15.560) for aPS/PT, 4.204 (1.250–14.148) for IgG aCL, 1.809 (0.354–9.232) for IgM aCL, and 7.246 (2.391–21.966) for aβ2GPI/CL. We conclude that, while all EIA performed in this study except IgM aCL are of potential value in assessing the risk of thrombosis, aPS/PT and aβ2GPI/CL seemed to be highly valuable in clinical practice, and that autoantibodies detected by anti-PT and anti-PS/PT are not completely identical