Molecular Events in the T Cell-Mediated Suppression of the Immune Response (original) (raw)
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Establishment of stable CD8+ suppressor T cell clones and the analysis of their suppressive function
Journal of Immunological Methods, 1992
Stable CD8 + suppressor T cell (Ts) clones were established by a relatively simple method. Keyhole limpet hemocyanin (KLH)-primed spleen cells from C3H mice were depleted of B cells and CD4 + T cells by panning and cytotoxic treatment, and the resulting CD8 + T cells were periodically stimulated with antigen and irradiated syngeneic spleen cells followed by manifestation in interleukin-2 (IL-2) containing medium. T cell clones with a definite suppressor function were established by limiting dilution. They were defined as classical effector type Ts of CD8 + phenotype as they had constant and definite suppressor functions in antigen-induced T cell proliferation and specific antibody response against T cell-dependent antigens without detectable cytotoxic activity against both antigen presenting cells (APC) and helper T cells (Th). They showed no helper activity for B cells and produced no detectable helper type lymphokines such as IL-2 and IL-4. CD8 ÷ Ts clones were able to inhibit the antigen-induced IL-2 production of normal and cloned T cells. Their suppressive activity was antigennonspecific and major bistocompatibility complex-unrestricted. CD8 ÷ Ts clones were also able to suppress the proliferative response of Th clones induced by immobilized anti-T cell receptor (TcR) and anti-CD3 mAbs but not the response induced by concanavalin A (ConA) and IL-2. All the CD8 + T cell clones established independently utilized the TcR V/38 gene. Syngeneic antigen presenting cells could induce proliferation of these CD8 + clones, which was blocked by anti-CD8 and anti-l-A k monoclonal antibody (mAb) but not by anti-class I mAbs. The stimulation of CD8 ÷ Ts clones with immobilized anti-CD3 resulted in the release of a suppressor factor(s) that potently inhibited the antigen-induced proliferation of CD4 ÷ Th clones and the in vitro secondary antibody formation.
The distinctive specificity of antigen-specific suppressor T cells
Immunology Today, 1991
Although suppressor T cells have been cloned in only a few instances, the existence of a functional cadre ofT cells that acts to downregulate the immune response is well documented. In this review Eli Sercarz and Urszula Krzych describe studies on suppressor T-cell (Ts-cell) specificity that provide some support for the conclusion that the T s cell is a distinctive cell type with an expressed repertoire that is different from that expressed by helper T (TIq) cells. They go on to explore the interaction between cells recognizing Ts-cell-inducing determinants (SDs) and TH-cell-inducing determinants (HDs), and their relationship to immunogenicity and Ir gene effects. In addressing the question of the specificity of T cells with suppressive function, a distinction must first be drawn between CD8 + and CD8-suppressor T cells. In both mouse and human systems, the distincnon between CD4 + suppressor inducer T (Tst) cells and CD8 + suppressor precursor T (or the effector cells themselves, TsE cells) cells has been clearly made; the inducer Tst cells have been shown to be necessary for activation of precursors of the effector cell, TsE 1,2. Likewise, the expression of different surface markers by CD4 + Trt and CD4 + Tst cells correlates with the functional disparity of these cells 3, although there is evidence that the CD4 + Tsl cells may be a late stage of the CD4 + helper T cell and may, therefore, be expected to have the identical specificity for antigen. This review is restricted to the specificity of 'professional' CD8 + Ts-cell precursors and effectors for nominal protein antigens whose primary structures have been defined, and their specificity relationships to CD4 + cells. The specificity of CD4 + 'nonprofessionals' such as TH1 and Trt2 cells, which do exhibit mutually inhibitory, cytokine-related suppressive activities 4-6 will not be considered nor will the interesting generalization that mouse and human Tst cells are E(DQ)-restricted rather than A(DR)-restricted be discussed 7,8. Criteria for defining SDs Induction by fragments or peptides from the antigen The first report that a portion of a Ts-cell-inducing protein antigen could substitute for the whole molecule in the induction of suppressor T cells concerned Escherichia coli 13-galactosidase (GZ)9,1°: a cyanogen bromide peptide of GZ, CB-2 (amino acids 3-92), induced Ts cells that could nullify, in vitro, the antibody response to the hapten fluorescein within the antigen GZfluorescein isothiocyanate (FITC), as demonstrated in cell-mixing experiments with GZ-primed helper T cells. Simultaneously, analysis of the anti-hen egg lysozyme (HEL) response in a nonresponder mouse strain (C57BL/6, H-2 b) produced evidence that a proteolytic fragment (N-C = 1-17: Cys6-Cys127: 120-129) from HEL could mimic the native molecule in the induction of suppression 11. This supported the concept that Phe3 was important for the induction of suppression, based on the
The Journal of Immunology
Culture supernatants generated by alloantigenic or lectin stimulation of a cloned helper T lymphocyte, designated L2, contain interleukin 2 (IL 2), granulocyte/macrophage colony-stimulating factor (CSF), B cell stimulating factor (BCSF), macrophage (Ia+)-recruiting factor (MIRF), (Ia+)-inducing activity, gamma-interferon, Fc receptor-enhancing activity, macrophage migration inhibitory factor (MIF), macrophage activation factor (MAF), interleukin 3 (IL 3), and a factor responsible for prolonging the synthesis and secretion of the fourth and second components of complement by guinea pig peritoneal macrophages. Erythropoietin was not detected. A spontaneously arising variant of L2, designated L2V, produces much lower quantities of macrophage-stimulating activities, IL 2, and interferon. However, when compared to L2, L2V produces much higher levels of BCSF, equivalent amounts of IL 3, and slightly smaller amounts of CSF. Unlike L2V, a cytolytic clone, designated L3, secretes lymphokines...
Functionally distinct human T cell clones that produce lymphokines with IL-2-like activity
Human Immunology, 1984
Various functionally distinct human T cell clones derived from in vitro mixed leukozyte cultures are found to secrete lymphokines with detectable Interleukin-2 (IL-2)-like activity upon antigenic stimulation. These lymphokine producing clones are not only dependent on exogenous growth factors provided in the form of crude phytohemagglutinin (PHA)-induced spleen conditioned medium for growth but can themselves be driven to proliferate by their own lymphokines. The induction of lymphokine production appears to be antigen-specific and the lymphokines secreted are believed to contain nonantigen and nonspecies specific IL-2-1ike activity. We show here that IL-2-like lymphokines are produced by a subset ofT lymphocyte clones, i.e., the help-independent cytotoxic T cells clones that have the capacity to proliferate to, as well as to lyse, the original sensitizing cells. In addition, other T cell clones capable of producing active lymphocytes include those clones that have the T helper cell characteristics, i.e,, can undergo antigen-induced proliferation but are not cytotoxic; in the presence of lectin (PHA), however, some helper T cells (Th) but not others, can express lectin-dependent cell-mediated lysis. Finally, yet another subset of T lymphocytes, the help-dependent cytotoxic T cell clones that cannot proliferate to antigenic stimulation, was found to produce no detectable IL-2-like activity.
Downregulation of helper T cells by an antigen-specific monoclonal Ts factor
Cellular Immunology, 1991
The findings of previous studies in this laboratory demonstrating that conjugates of human monoclonal (myeloma) IgG (HlgG) and monomethoxypolyethylene glycol (mPEG) were able to induce in mice antigen-specific tolerance and CD8+ suppressor T (Ts) cells were confirmed in the present study. An extract (TsF) of a nonhybridized clone of Ts cells (viz., clone 23.32), which had been derived from spleen cells of mice tolerized with HIgG(mPEGh6, was shown to possess antigen-specific suppressive activity. This monoclonal TsF was able to specifically suppress in vitro antibody formation only if it was present from the beginning of the culture. From the results of the cellular dissection of the system used it was concluded that (i) the TsF had no effect on fully differentiated primed B cells or plasma cells, and (ii) the TsF inactivated carrier-primed Th cells when the culture contained concomitantly naive CD8+ T cells, accessory cells, and antigen. These data support the view that the monoclonal TsF exerted its downregulating effect on Th cells only if it could first interact with a CD8+ T cell, in the presence of accessory cells and antigen.
Journal of Experimental Medicine, 1983
Two antisera and a monoclonal antibody raised in BALB.K mice against cloned, major histocompatibility complex (MHC)-restricted, antigen-specific helper T cell lines are described. These antibodies are specific for individual cloned T cell lines and are potent inducers of T cell proliferation. The induction of T cell proliferation by these antibodies requires the presence of an adherent accessory cell. There is no H-2 restriction between this accessory cell and the cloned T cell, nor is this antibody-induced proliferation blocked by a monoclonal anti-Fc receptor antibody. The requirement for an accessory cell, however, is eliminated in the presence of an IL-1- or IL-2-rich supernatant. Thus this system allows the analysis of helper T cell activation with only a single cell type present. Anti-T cell sera also induce T cell-dependent B cell proliferation and immunoglobulin secretion. The induction of T cell-dependent B cell activation by these sera does not require H-2-matched T cells ...