Supplementary Table S1 from Concurrent Induction of Antitumor Immunity and Autoimmune Thyroiditis in CD4+CD25+ Regulatory T Cell–Depleted Mice (original) (raw)
Related papers
Cancer Research, 2005
When CD4 + CD25 + regulatory T cells are depleted or inactivated for the purpose of enhancing antitumor immunity, the risk of autoimmune disease may be significantly elevated because these regulatory T cells control both antitumor immunity and autoimmunity. To evaluate the relative benefit and risk of modulating CD4 + CD25 + regulatory T cells, we established a new test system to measure simultaneously the immune reactivity to a tumor-associated antigen, neu, and an unrelated self-antigen, thyroglobulin. BALB/c mice were inoculated with TUBO cells expressing an activated rat neu and treated with anti-CD25 monoclonal antibody to deplete CD25 + cells. The tumors grew, then regressed, and neu-specific antibodies and IFN- ;-secreting T cells were induced. The same mice were also exposed to mouse thyroglobulin by chronic i.v. injections. These mice produced thyroglobulinspecific antibody and IFN- ;-secreting T cells with inflammatory infiltration in the thyroids of some mice. The immune responses to neu or thyroglobulin were greater in mice undergoing TUBO tumor rejection and thyroglobulin injection than in those experiencing either alone. To the best of our knowledge, this is the first experimental system to assess the concurrent induction and possible synergy of immune reactivity to defined tumor and self-antigens following reduction of regulatory T cells. These results illustrate the importance of monitoring immune reactivity to self-antigens during cancer immunotherapy that involves immunomodulating agents, and the pressing need for novel strategies to induce antitumor immunity while minimizing autoimmunity.
Induction of CD4 +CD25 + T Regulatory Cells with CD103 Depletion
Journal of Surgical Research, 2010
Background. M290SAP, a murine CD103 antibody conjugated with the immunotoxin saporin, has been found to induce the indefinite acceptance of transplanted pancreatic islets in mice. We sought to understand the underlying mechanism of this alloacceptance, particularly with respect to the CD4 CD25 T regulatory phenotype.
CD4+ CD25+ CD62+ T-Regulatory Cell Subset Has Optimal Suppressive and Proliferative Potential
American Journal of Transplantation, 2004
CD4 + CD25 + regulatory T cells (Treg) are potent suppressors, and play important roles in autoimmunity and transplantation. Recent reports suggest that CD4 + CD25 + Treg are not a homogeneous cell population, but the differences in phenotype, function, and mechanisms among different subsets are unknown. Here, we demonstrate CD4 + CD25 + Treg cells can be divided into subsets according to cell-surface expression of CD62L. While both subsets express foxp3 and are anergic, the CD62L + population is more potent on a per cell basis, and proliferates and maintains suppressive function far better than the CD62L-population and unseparated CD4 + CD25 + Treg. The CD62L + population preferentially migrates to CCL19, MCP-1 and FTY720. Both CD62L + and CD62L-subsets prevent the development of autoimmune gastritis and colitis induced by CD4 + CD25-CD45RB high cells in severe combined immunodeficiency (SCID) mice. Overall, these results suggest CD4 + CD25 + Treg are not a homogenous cell population, but can be divided into at least two subsets according to CD62L expression. The CD62L + subset is a more potent suppressor than the CD62L-population or unfractionated CD4 + CD25 + Treg cells, can be expanded far more easily in culture, and is more responsive to chemokine-driven migration to secondary lymphoid organs. These properties may have significant implications for the clinical manipulation of the CD4 + CD25 + CD62L + cells.
Parameters controlling the programmed death of mature mouse T lymphocytes in high-dose suppression
Cellular Immunology, 1995
induction, increased proliferation, and greater suppression at high antigen doses. Profound loss of cells at high antigen dose was found to require at least 48 to 72 hr to develop. Antigen add-back experiments showed that strong T cell receptor reengagement of activated, cycling cells was essential for proliferative suppression and cell loss. Increasing the ratio of APC:T lymphocytes to 50: 1 augmented cell death. For antigen-induced death of lymph node T cells, fresh T-depleted splenocytes were more effective than splenocytes that had been irradiated or treated with mitomycin C. Thus, T lymphocyte apoptosis at high antigen doses is a function of the activation response of the T lymphocyte as well as the efficiency of antigen presentation by the APC. These results strengthen the theory that apoptosis takes part in a feedback regulatory mechanism that has been called propriocidal regulation, which limits T cell expansion at high antigen doses. o 1995 Academic PWS, IIIC. 3 Abbreviations used: APCs, antigen-presenting cells; IL-SF& interleukin-2 receptor 01 chain; TCR, T cell receptor; dThd, thymidine; PCC, pigeon cytochrome c; LNTC, lymph node T cells; MBP, myelin basic protein.
Transplantation Journal, 2010
Rabbit antithymocyte globulin therapy (rATG) is a potent lymphocyte-depleting agent commonly used following renal transplantation to reduce the risk of acute rejection. Standard doses (7-10 mg/kg) of rATG result in profound lymphopenia and predispose patients to infection and malignancy. The effects of lower doses of rATG (LoD-rATG, 3-5 mg/kg) on peripheral blood lymphocytes (PBL) are as yet unknown. In this prospective clinical trial, PBL subsets were characterized by flow cytometry over 12 months following LoD-rATG therapy. All patients were initially treated with standard doses of tacrolimus, mycophenolic acid, and prednisone. At 3 months, patients were randomized to either lower doses of tacrolimus or sirolimus to examine the effects of maintenance immunosuppression on PBL reemergence. LoD-rATG therapy resulted in prolonged suppression of CD19 ϩ B cells, total CD3 ϩ T cells, as well as naïve and memory CD4 ϩ T cell and CD4/CD25/Foxp3 ϩ T-regulatory subsets irrespective of chronic immunosuppressive therapy. Selective depletion was only noted in the CD4CD45RA ϩ naïve T-cell subset resulting in an altered memory/naïve CD4 ϩ ratio. LoD-rATG failed to deplete CD8 ϩ T cells, which increased their relative contribution to the total CD3 ϩ pool. All other lymphocyte subsets maintained near normal proportions. Thus, LoD-rATG therapy may lessen the adverse effects of full dose rATG while maintaining overall efficacy.
Immunobiology, 2013
CD4 + CD25 + Foxp3 + T regulatory cells (Tregs) and CD1d-restricted invariant natural killer T (iNKT) cells are two cell types that are known to regulate immune reactions. Depletion or inactivation of Tregs using specific anti-CD25 antibodies in combination with immunostimulation is an attractive modality especially in anti-tumour immunotherapy. However, CD25 is not expressed exclusively on Tregs but also on subpopulations of activated lymphocytes. Therefore, the modulatory effects of the specific anti-CD25 antibodies can also be partially attributed to their interactions with the effector cells. Here, the effector functions of iNKT cells were analysed in combination with anti-CD25 mAb PC61. Upon PC61 administration, ␣-galactosylceramide (␣-GalCer)-mediated activation of iNKT cells resulted in decreased IFN-␥ but not IL-4 production. In order to determine whether mutual interactions between Tregs and iNKT cells take place, we compared IFN␥ production after ␣-GalCer administration in anti-CD25-treated and "depletion of regulatory T cell" (DEREG) mice. Since no profound effects on IFN␥ induction were observed in DEREG mice, deficient in FoxP3 + Tregs, our results indicate that the anti-CD25 antibody acts directly on CD25 + effector cells. In vivo experiments demonstrated that although both ␣-GalCer and PC61 administration inhibited TC-1 tumour growth in mice, no additive/synergic effects were observed when these substances were used in combination therapy.
MRL-.lpr/Ipr (lpr) mice develop profound lymphadenopathy resulting from the accumulation of CD4CD8-(double-negative, DN) cells in the peripheral Iymphoid organs. Earlier studies from our laboratory demonstrated an increased proportion of DN cells in the thymus of lpr mice with age. Inasmuch as the DN thymocytes constitute a heterogenous population of cells, in the present study, wt: investigated the TCR phenotype of DN thymocytes and their responsiveness to activation through the TCR. The DN thymocytes of young (1 month of age) Ipr mice contained -65% CD3+ cells of which -60% were ofl-TCR+ and -39% were y&TCR+ as detected by using pan anti-TCR mAbs. In old (4-6 months of age) or young MRL-+/+ mice, similar proportions of CD3+, o/3-or yb-TCR+ DN thymocytes were detected. Interestingly, however, in old (4-6 months of age) lpr mice, the CD3+ T cells increased to -86% and the majority of these (-81%) were a@TCR+ and only -3% were y&TCR+. Also, in old lpr mice, there was a lo-fold increase in the absolute number of c&TCR+ DN cells in the thymus, whereas, the absolute number of y& TCR+ DN cells in the thymus did not alter significantly. Furthermore, a majority (-84%) of the old Ipr DN thymocytes expressed CD45R, similar to the peripheral DN T cells. In contrast, only a small number (-1%) of DN thymocytes from young Ipr or MRL-+/t mice expressed CD45R. The DN thymocytes from young lpr or MRL-+/+ mice demonstrated strong and similar proliferative responsiveness to stimulation with PMA + calcium ionophore or PMA + IL-2, or to immobilized mAb directed against the TCRs (CD3, @3 and 7s). In contrast, the DN thymocytes and the DN peripheral T cells from old lpr mice demonstrated marked defect in responding to the above stimuli. The present study suggests that with the onset of lymphadenopathy, the DN cells in the thymus of old Ipr mice are increasingly skewed toward the &TCR repertoire, the majority of which express CD45R and respond poorly to mitogenic stimuli or when activated through the TCR. It is suggested that migration of such cells continuously to the periphery may result in severe lymphadenopathy seen in old MRL-lpr/lpr mice. 0 1991 Academic press, IIIC. r This work was supported, in part, by NIH Grants CA 45009 and CA 45010 awarded to M.N. and P.S.N.