Evidence for distinct epitopes on human IgG with T cell proliferative and suppressor function

The Fc or pFc' fragments of the human IgG were demonstrated to exert different effects on murine T lymphocyte subsets. Thus, murine lymph node (LN) T cells were specifically induced to proliferate in vitro to pFc' after priming in vivo. This proliferation could be inhibited, either by depleting the responding LN population of macrophages, or by monoclonal antibodies specific for responder haplotype Ia antigenic determinants. Priming in vivo and subsequent restimulation in vitro with Fc resulted in the activation of a suppressor T cell subpopulation which, in an antigen-specific manner, could highly suppress proliferative responses. T cell subset isolation showed that the pFc'-specific proliferation was performed by Lyt-1+2- cells whereas the suppressor Fc-specific cells were of Lyt-1-2+ phenotype. Our data demonstrate that distinct epitopes on the human gamma chain induce either Ir gene-restricted T cell proliferation (pFc' fragment) or T cell suppressor function (Fc fragment).     

Ontogeny of human suppressor inducer T cell subset

A T cell subset (T4+,2H4+) has recently been identified, which acts as an inducer of T8+ suppressor cells; however 2H4 molecules have not been detected in thymuses from normal individuals or on the surface of immature thymocyte clones. In the present study, T4+,2H4+ and T8+,2H4+ cells have been found in maternal and new-born blood samples. However, only a small percentage of 2H4+ cells were detected in human fetal thymus, bone marrow, liver and spleen, thus suggesting that T cells acquire these molecules only in circulation and at a late stage of maturation.     

Evidence for the immunosuppressive role of nicotine on human dendritic cell functions

Nicotine alters a wide range of immunological functions, including innate and adaptive immune responses. To date, no studies have been reported showing the immunoregulatory effects of nicotine on dendritic cells (DCs), which are critical cells for initiation of cell-mediated immunity against infection and neoplastic diseases. In this work, we report that, in a nicotinic environment, monocyte-derived DCs manifest lower endocytic and phagocytic activities. Interestingly, although immature DCs undergo maturation in response to bacterial antigen lipopolysaccharide, they produce decreased levels of pro-inflammatory cytokines, notably interleukin-12, and reveal a reduced ability to stimulate antigen-presenting cell-dependent T-cell responses. Importantly, the reduction in T-cell responses is associated with a diminished ability of DCs to induce differentiation and expansion of type 1 T cells, as evidenced by a decreased frequency of interferon-gamma-producing effector cells. These results strongly suggest that nicotine can exert its immunosuppressive effects on immune surveillance through functional impairment of the DC system.     

Evidence of diminished suppressor T cell activity in patients with atopy and SLE

The T cell mitogen concanavalin A (Con A) was added to lymphocytes pre-cultured for 24 hours in vitro in tissue culture medium. Delayed addition of the mitogen resulted in an enhanced lymphocyte activation measured by incorporation of radioactive precursors of DNA. T cells isolated by rosetting with sheep erythrocytes also exhibited this enhancement. In a limited study, lymphocytes from both atopic patients and those with systemic lupus erythematosus (SLE) showed little or no enhanced responsiveness to Con A. The possibility that some patients with atopy and SLE possess defective suppressor T cells is discussed in the light of these data.     

A marmoset T lymphoma which functions as a human amplifier T cell

A long-term in vitro grown T cell line derived from a cotton-topped marmoset (Saguinus oedipus) infected with Herpesvirus saimiri was fond to share surface antigens with human amplifier T cells and to augment the capacity of human B cells to secrete immunoglobulin. This is the first demonstration of T/B collaboration across such a large phylogenetic barrier and might have interesting implications for understanding the nature of molecular interactions mediating cell/cell cooperation.     

Requirement for OKT8+ suppressor cell proliferation for suppression by human newborn T cells.

The percentage of cells bearing the suppressor phenotype OKT8+increases in PWM-stimulated cultures of human newborn lymphocytes. Prevention of this increase either by adding 50 microM deoxyguanosine to the cultures of by pretreating the newborn cells with OKT8 and complement reduced the suppressor activity of newborn T cells. These results suggest that newborn T cells are not intrinsically suppressive, but that they become so in vitro after stimulation by PWM.     

Peripheral tolerance in T cell receptor-transgenic mice: Evidence for T cell anergy

T cell tolerance can be induced in adult mice by injection of soluble antigenic peptide. The underlying mechanism has been difficult to establish in normal mice due to the low precursor frequency of T cells specific for any given antigen. Therefore, we examined peripheral tolerance in mice transgenic for a T cell receptor specific for a cytochrome c peptide bound to I-E^k. Antigen-specific hyporesponsiveness could be induced in the transgenic mice. We followed the transgene-bearing T cells with a clonotypic monoclonal antibody and found similar numbers of clonotypic T cells in tolerized and control mice. To prevent de novo differentiation of T cells we analyzed thymectomized mice in which antigen-specific hyporesponsiveness was induced. Our analysis of thymectomized transgenic mice showed that antigen-specific T cell hyporesponsiveness following injection of peptide intravenously is not caused by gross elimination of T cells. These data provide evidence for the role of anergy in peripheral tolerance.     

Helper and suppressor functions of human mononuclear cells depleted of antigen-binding T8+ cells.

We have utilized the antigen-binding function of a subset of T8+ cells to remove these cells in vitro from human peripheral blood mononuclear cells. This was carried out by treating the cells with streptococcal antigen (SA), monoclonal anti-SA antibody and complement. The concentration of SA binding to T8+ cells differs with the HLA-DR type of the cells: 1 ng SA binds to DRw6+ cells and elicits T helper activity, whereas 1000 ng SA elicits T suppressor activity, in an assay for antibody-forming cells. After depletion of the antigen-binding cells by the SA-specific complement-dependent killing technique, the helper function of the DRw6+ cells was lost but suppression was elicited not only by 1000 ng but also by 1 ng SA. Similarly, DRw6- cells which bind 1000 ng SA to elicit helper activity and 1 ng to elicit suppression, when depleted of the SA-binding cells, resulted in loss of helper activity but again, suppression could be elicited by both 1000 and 1 ng SA. We suggest that treatment of mononuclear cells with antigen, the specific antibody and complement removes the T8+ antigen-binding cells which present antigen to T helper cells and results in the loss of helper function. Suppressor function is however, not only retained with the original concentration of SA but also expressed with that required to elicit helper function in the untreated cells. These findings are consistent with our hypothesis that the antigen-binding and presenting T8+ cells also function as contrasuppressor cells. Thus, the T8+ subset of cells have a dual function, to present antigen and to activate T helper cell function, and to prevent suppressor cells from inhibiting the helper cells.     

Cimetidine abrogates suppressor T cell function in vitro

Cimetidine increased the [3H] thymidine incorporation of normal human mononuclear cells in culture both when unstimulated or when under the stimulus of phytohemagglutinin or pokeweed mitogen (PWM). It also increased their supernatant immunoglobulin production under PWM stimulus. These effects were higher when the cells were preincubated with cimetidine than when it was added simultaneously. To determine if this effect of cimetidine reflects an abrogation of suppression we studied concanavalin-A-induced suppressor function of normal mononuclear cells using both [3H] thymidine incorporation and immunoglobulin synthesis as indicator systems and found that preincubation with cimetidine caused significant decrease in suppressor cell function in both systems.     

Seasonal variation in suppressor T cell subsets and non-specific suppressor cell function in hay fever sufferers

The helper/suppressor T cell ratio, as defined by monoclonal antibodies, was significantly higher in hay fever sufferers compared with controls (P less than 0.05), but only during or shortly after the pollen season. This was due to a reduction in the suppressor subset, which returned to control values in the winter. There was no significant difference in the non-specific concanavalin A-induced suppressor cell function compared with controls. The mean summer value was significantly lower than the winter value (P less than 0.05), but we cannot be sure that this was not the result of changes in laboratory conditions. No relationship was found between T cell subsets or suppressor cell function and total or specific IgE levels, or between T cell subsets and suppressor cell function. Our findings suggest that in hay fever, reduction in suppressor cell numbers and function is a secondary phenomenon.     

Evidence for regulation of the autoimmune anti-erythrocyte response by idiotype-specific suppressor T cells in NZB mice

The present study demonstrates that specific CD8+, CD4- suppressor T cells (Ts) actively regulate the autoimmune anti-mouse red blood cell (MRBC) antibody response in spleen cell populations of young, Coombs-negative NZB mice. These Ts appear to bind a monoclonal NZB autoantibody (G-8 mAb) to unmodified MRBC which expresses a dominant idiotype (Id) in the spontaneous anti-MRBC autoantibody response of NZB mice. Treatment of normally nonauto-responsive spleen cells from young NZB mice with the G-8 mAb + C prior to culture allows these cells to develop, in 4-5 days, an autoantibody response to MRBC. The level of response obtained after depletion of the G-8-binding cells is comparable with that obtained after generalized depletion of Ts by treatment with anti-CD8 + C, suggesting that the G-8-binding cells make up a major portion of the regulatory Ts in this response. Yet, G-8 + C treatment depletes a very small subset of cells and not the total CD8+ T cell population. The regulatory cells appear to be neither isotype nor allotype specific, nor do they appear to have MRBC antigens bound to or expressed on their membranes. Rather, these cells are more likely G-8 idiotype specific. The regulatory G-8-binding cells are CD8+ T cells, not B cells. Furthermore, Ts-enriched populations when depleted of G-8-binding cells lose their ability to suppress in vitro anti-MRBC responses of spleen cells from Coombs-negative NZB mice depleted of CD8+ cells, as well as those of unfractionated spleen cells from Coombs-positive NZB mice.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of T cell-mediated cytotoxic allograft responses. I. Evidence for antigen-specific suppressor T cells

Murine lymph node cells draining a local lymphoid cell allograft (LNd) exhibited weak cytolytic activity when tested immediately after surgical removal, However, upon mere in vitro cultivation, high cytotoxic activity developed. The in vitro generation of cytotoxic activity could be inhibited by treatment of the cells with mitomycin C. Upon transfer into a primary mixed lymphocyte culture, mitomycin C-treated LNd cells effectively suppressed the induction of cytotoxic T lymphocytes (CTL). Using the velocity sedimentation technique at 1 × g the suppressor cells could be confined to the blast cells within LNd cells, the sensitized prekiller T cells being nonsuppressive. Results derived from independent experimental approaches suggested that the in vivo sensitized blast suppressor cells exhibited an immunological specific suppression, i.e. they selectively suppressed the in vitro induction of CTL reactive towards those H-2 transplantation antigens against which the suppressor cells had been immunized. Thus, antigen-specific suppressor cells (which were Thy-1.2 positive) appeared to be specifically activated during the in vivo sensitization procedure.     

Phytohaemagglutinin-induced proliferation of human T lymphocytes: differences between neonate and adults in accessory cell requirements.

The accessory cell requirements of human neonatal T lymphocytes were compared with those of adult T lymphocytes in lectin-induced polyclonal activation. It was found that purified neonatal Esh rosette positive lymphocytes were not activated into a proliferative response by the lectin phytohaemagglutinin (PHA), by phorbol ester (TPA) or by conditioned medium containing T cell growth factor activity (TCGF-CM). A proliferative response to PHA was obtained in the presence of a suitable accessory cell (AC) such as the plastic adherent, monocyte enriched population or the sIg positive lymphocyte population, both of which were shown by cellular titrations to be equally effective. Optimal proliferative responses to PHA could also be obtained, in the absence of accessory cells, by addition of TPA or TCGF-CM. Neonatal T lymphocytes gave highly reproducible responses and this could be achieved effectively by simple separation procedures not involving further subfractionation of the responding Esh+ lymphocyte population. The exquisite accessory cell dependence of these cells demonstrated in this investigation provides a readily available human model system for the evaluation of the variables involved in T lymphocyte activation and a sensitive assay for measuring accessory cell activity.