Appearance Of Suppressor Research Articles

IL-15 temporally reorients IL-10 biased B-1a cells toward IL-12 expression.

Interleukin (IL)-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-1a cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-1a cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin (Siglec)-G, an inhibitor of cell activation that is present on B-1a cells. The IL-15 receptor CD122 was stimulated on B-1a cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-10 is responsible for the long term survival of B-1a cells in culture, which is initially promoted by IL-15. The upregulation of IL-10 was followed by the appearance of suppressor of cytokine signaling (SOCS)1 in the presence of IL-15 and the loss of IL-10. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-1a cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death (PD)-1 and its ligand PD-L2 were features of a predominantly IL-10 response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL-15. Collectively, the data implicate IL-15 as the master cytokine that induces B-1a cells to mount a mucosal immune response.

Regulation of cytokine gene expression in experimental autoimmune encephalomyelitis.

We previously reported that recovery of Lewis rats from experimental autoimmune encephalomyelitis (EAE) is associated with the appearance of suppressor T cells (Ts). These Ts secrete TGF-beta which down-regulates the production of inflammatory cytokines by the effector T cells that mediate this disease. In the present study, we immunized Lewis rats with myelin basic protein (MBP)+CFA, and evaluated purified T cells and MBP-activated spleen cells (SpC) during the paralytic phase (day 12) and after recovery (days 30-33) for TGF-beta and interferon (IFN)-gamma mRNA. We used reverse transcriptase-polymerase chain reaction (RT-PCR), quantitated on the basis of beta-actin mRNA. Abundant IFN-gamma mRNA was present in MBP-activated SpC obtained on day 12. In contrast, only trace IFN-gamma mRNA was detected in day 30 activated SpC, and no IFN-gamma mRNA was present in purified, nonactivated T cells obtained at either time. The level of IFN-gamma mRNA correlated with secretion of IFN-gamma as determined by ELISA on SpC culture supernatants, and with severity of adoptively transferred EAE by the activated SpC. Thus, it appears that IFN-gamma mRNA is both transcribed and translated in response to antigen activation, resulting in secretion of IFN-gamma by the disease-inducing Te. In contrast, when we used RT-PCR to investigate the expression of TGF-beta mRNA, we found the transcript present in isolated T cells and MBP-activated SpC obtained from rats at both days 12 and 30. The presence of TGF-beta mRNA at time points corresponding to both clinical EAE and recovery suggests post-transcriptional regulation of the production of this immunoregulatory cytokine.

Host Response to Myeloma: I. Induction of Cytotoxic and Suppressor T Cells by In Vivo Immunization with MOPC 104E Plasmacytoma

Spleen cells from BALB/c mice immunized with mitomycin C-treated MOPC 104E plasmacytoma cells demonstrated negligible cytotoxic activity (less than 10% specific cytotoxic activity) in the 51Cr release assay. These cells exhibited increased cytotoxic activity when they were secondarily sensitized in vitro with mitomycin C-treated MOPC 104E cells. Spleen cells from normal mice showed tumor-specific cytotoxic activity when cocultured with mitomycin C-treated tumor cells at the optimal responder to stimulator ratio of 25:1. The level of cytotoxic activity obtained by in vivo primed and secondarily in vitro sensitized spleen cells did not exceed the level of activity obtained by in vitro primary sensitized cells. Significant suppression of the cytotoxic activity of in vitro primary sensitized cells was observed when cocultured with in vivo primed spleen cells during primary sensitization in vitro at a responder to suppressor cell ratio of 1:1. Suppressor cells of in vivo primed mice were removed by treatment with anti-Thy 1.2 and complement. These results suggest that spleen cells from in vivo primed mice consisted of at least two subpopulations of cells, a cytotoxic (prekiller) and suppressor T cells. Attempts to induce cytotoxic cells in vivo might have failed because of the appearance of suppressor T cells.

Studies on the role of antigen-presenting cells in the systemic suppression of contact hypersensitivity by UVB radiation.

Exposure of mice to UVB radiation produces a highly selective, systemic immunosuppression associated with the appearance of suppressor T lymphocytes. Suppression of delayed hypersensitivity to hapten-coupled syngeneic cells has been shown to result from an altered distribution of antigen-presenting cells. The purpose of this study was to determine whether an alteration in the activity of antigen-presenting cells could account for the systemic suppression of contact hypersensitivity (CHS) by UVB radiation. Fluorescein isothiocyanate (FITC) was used for contact sensitization because it uses different antigen-presenting cells than does oxazolone to induce CHS. Our previous studies demonstrated that CHS to oxazolone was suppressed by UVB irradiation. In these studies, we show that exposure of mice to UVB radiation before epicutaneous application of FITC onto unirradiated skin markedly decreased the CHS response to FITC painted on unexposed ears. Cyclophosphamide-sensitive suppressor T cells were detectable in the spleens of mice exhibiting decreased CHS. The antigen-presenting activity of cells in lymph nodes draining the site of epicutaneous sensitization (DLN cells) was assessed by injecting them into the hind footpads of syngeneic recipients and measuring the CHS response to FITC 6 days later. Viable DLN cells from UVB-irradiated, FITC-sensitized mice were equal to those from unirradiated, FITC-sensitized mice in their ability to induce CHS in normal recipients. No sensitization resulted when killed DLN cells were used for immunization, indicating that sensitization was not caused by reprocessing of antigen by host cells. We conclude that impairment of the CHS reaction in UVB-irradiated mice does not appear to be blocked at an initial step of antigen uptake, processing, or presentation, but must be impaired at some other step in the immunologic pathway.

IgE responses of malnourished mice: Immunogenic and tolerogenic effects of low-grade antigenic stimulation

Mice maintained on protein-restricted diets after weaning manifested normal IgE (and IgG) responses following intraperitoneal immunization under conditions of maximal antigenic stimulation, i.e., antigen adsorbed to adjuvant. However, antigenic challenge at levels closer to the stimulation threshold, employing soluble antigen alone, revealed marked differences between the immune competence of normal and malnourished animals. Diminished IgE responsiveness to soluble antigen in the malnourished mice was accompanied by enhanced susceptibility to the induction of antigen-specific tolerance associated with the appearance of suppressor T cells in the spleen. It is argued that enhanced susceptibility to suppressor T-cell induction under conditions of minimal antigenic stimulation may underlie the diminished IgE responsiveness of the malnourished animals.

Immunocompetent cells in uterine cervical lesions of human papillomavirus origin.

To elucidate the local immunological reactions operative in the human papillomavirus (HPV)-induced lesions of the uterine cervix, a total of 150 cervical biopsies containing a dysplastic or a neoplastic change with (CO, 97 cases) or without (NCO, 53 cases) a coexistent HPV lesion (a flat, an inverted or a papillomatous condyloma) were subjected to ANAE (acid alpha-naphthyl acetate esterase) staining of the immunocompetent cells; B and T lymphocytes, mononuclear phagocytes (MPS cells). In addition, HPV antigens were demonstrated by an indirect immunoperoxidase-PAP method. Age of the patients did not influence the proportions of B, T and MPS cells. Degree of epithelial atypia was inversely related to proportion of B cells in NCO but not in CO series, and directly related to proportions of T cells in CO series, the latter T cell increase being most probably ascribable to the appearance of suppressor T cells. Unlike in the different types of skin warts (caused by divergent HPV types), the type of the cervical condyloma did not affect the proportions of B, T and MPS cells, suggesting a common HPV type as a causative agent of the latter. MPS and T cells were more numerous in HPV-positive condylomas than in HPV-negative ones, supporting the concept that cell-mediated immune mechanisms recognize the surface antigens of the virus-transformed cells coded by the viral genome in the host cell nuclei (HPV+). The findings are discussed in terms of the immune mechanisms involved in rejection of HPV lesions in general, and those of the uterine cervix especially. The full significance of these mechanisms can only be understood when adequate follow-up data of the lesions are at hand.

Regulation of in vitro generation of cell-mediated cytotoxicity. II. Characterization of thymosin-induced suppressor T cells

Thymosin fraction 5 can induce the appearance of suppressor T cells capable of regulating the in vitro generation of cytotoxic T lymphocytes (CTL) in a 5-day allogeneic or syngeneic mixed lymphocyte-tumor culture (MLTC). Characterization of the suppressor cell population demonstrated it to be a nonadherent, cyclophosphamide-sensitive T cell. In addition, adult thymectomy (Tx) eliminated suppressor cell precursors in spleen, pointing to a direct thymic dependence of the population. Kinetics studies showed that the thymosin influence aas necessary for at least the first 12 hr of culture ior optimal suppression to occur. The in vitro-generated suppressor T cells were antigen specific and could be generated with spleen, thymus, or lymph node cell preparations, suggesting the wildsped existence of a gluotory T-cell population under direct Humoral thymic control.

Regulation of the Immune Response to Tumor Antigen

Abstract The nature and function of suppressor factor(s) elaborated by suppressor T cells in response to certain chemically induced tumors have been further defined. Thus, suppressor factor(s) specific for the S1509a methylcholanthrene-induced fibrosarcoma have been shown to bear determinants encoded by the I-J subregion of the murine MHC since suppressive activity is removed by passage of the factor through an immunoadsorbent composed of anti-I-Jk coupled to Sepharose. No loss of activity was observed after passage of factor through control columns composed of normal mouse globulin. Furthermore, activity could be recovered from the relevant immunoadsorbent by elution with high salt. The administration of crude suppressor factor(s) to normal animals for 4 days resulted in the development of a population of suppressor cells that act in a manner analogous to the suppressor cell population used for production of factor. These factor-induced suppressor cells are T cells and exhibit an antigen specificity similar to that displayed by the tumor-induced suppressor cells. Thus, tumor-specific suppressor factor(s) bear I-J determinants and are capable of inducing the appearance of suppressor T cells in the nontumor-bearing host, which may then act in a specific manner to limit host responsiveness to tumor antigen.

Adult thymectomy prevention of the appearance of suppressor T cells which depress contact sensitivity to picryl chloride and reversal of adult thymectomy effect by thymus extract.

Suppressor cells, which depress the passive transfer of contact sensitivity appear in the lymph nodes and spleen of mice injected with picryl sulfonic acid (PSA). These cells produce a soluble suppressor T cell product (s-TCP), and immune lymph node cells incubated in s-TCP fail to transfer contact sensitivity. This paper shows that the appearance of suppressor T cells following the injection of PSA was prevented by adult thymectomy (ATx). ATx also limited the production of s-TCP. However, ATx had no effect on the DNA synthesis which occurs in the lymph nodes of mice injected with PSA. The adverse effect of ATx on suppressor cells was completely reversed by a neonatal thymus graft placed under the renal capsule and partially reversed by grafts given 600 r in vitro and to a limited extent by grafts given 1000 r. The injection of thymus extract also reversed the effect of ATx whereas splenic extract was inactive. It is suggested that the suppressor T cell which depresses contact sensitivity is dependent on the presence of the thymus because it requires a thymus hormone, and not primarily because it belongs to a short-lived population which is rapidly renewed by cells coming from the thymus.