Suppressor Effector Cells Research Articles

MHC- and Igh-Unrestricted Interaction between L3T4 +, Lyt-2 - Ts Inducer Cells and L3T4 -, Lyt-2 + Ts Effector Cells is Required for T Cell-Depend

This paper describes the characteristics of T suppressor inducer (Ts ind) cells which caninteract with T suppressor effector (Ts eff) cells and thereby can account for suppression of delayed-type hypersensitivity (DTH) to alloantigens. Adoptive transfer of spleen cells from mice intravenously (i.v.) injected with allogeneic spleen cells one day earlier induced an antigen-specific state of suppression in the recipients. This became apparent when DTH was induced by subcutaneous (s.c.) immunization of the recipients three days after transfer. The induction of suppression after adoptive transfer of spleen cells required Thy-1 +, L3T4 +, Lyt1 +2 - cells. These cells that by themselves did not exert a suppressive effect induced a state of suppression in recipient mice by activation of recipient-type Ts eff cells. Therefore, the former cell type was classified as Ts ind cell. When athymic nude mice were used as recipients, Lyt-2 + precursors of Ts eff cells had to be transferred together with the Ts ind cells to induce a state of suppression in these mice. The Ts ind cells could activate Ts eff cells in MHC- and Igh-incompatible recipients. The results are discussed in relation to previously described immunoregulatory T cell pathways.

Circulating T-Lymphocyte Sub-Subsets and NK-Like Cells in Renal Transplant Patients: Patterns Associated with Rejection

The patterns of circulating T sub-subset and NK-like cells were monitored in 87 renal transplant patients on a total of 122 occasions. Combinations of monoclonal antibodies were used in two-colour flow cytometric (FACS) analysis to define the major T helper/inducer and T suppressor/cytotoxic subsets and their activated counterparts, the T suppressor inducer and T suppressor effector sub-subsets, NK-like cells and their activated counterparts. In patients with rejection, the proportions of T suppressor inducer and T suppressor effector cells were less and the proportion of activated NK-like cells greater compared with cases exhibiting stable graft function, and these group differences were highly significant. Analysis with stepwise multivariate logistic regression showed that combinations of several functional/activated lymphocyte subsets allow a predictive diagnostic power which is superior to the use of single variables.

Regulation of the systemic immune response by visible light and the eye.

The injection of certain antigens into the anterior chamber (AC) of the eye results in the induction of antigen-specific suppressor T cells (Ts cells), which inhibit systemic delayed-type hypersensitivity (DTH). We have previously shown that down-regulation by Ts cells after AC injection with 2,4,6-trinitrophenol (TNP)-coupled spleen cells (TNP-Spl) is initiated by the intraocular activation of Ts inducer cells. These cells activate T suppressor-effector cells in the spleen that are responsible for suppressed DTH. With dark- and light-reared mice (Balb/c), we show that visible light has a direct effect on the intraocular T cell reaction that leads to systemic suppression. Our results show that if light is prevented from reaching the eye by dark rearing, by placing light-reared animals in the dark after AC injection, or by closing the eyelids of light-reared animals after AC injection, Ts cells are not activated. We show that light is responsible for establishing conditions in the eye that cause the preferential activation of Ts cells. The intraocular conditions established by light are not developmentally mandated as is visual development, but can be eliminated in adult light-reared animals by placing them in the dark for 18 h after AC injection. These conditions can also be induced in adult dark-reared animals by returning them to the light for just over 24 h before AC injection. These studies have important implications for understanding intraocular immune responses and possibly for the treatment of eye disease.

A role for L3T4 + T cells and their lymphokines in the generation of suppressor effector (Ts 3) cells

The cellular requirements for the in vitro induction of antigen-specific suppressor T cells were examined. Previous reports indicated that Ia-bearing macrophages and anti-idiotypic B cells are required as accessory cells to facilitate the generation of suppressor effector (Ts 3) cells which regulate the response to the 4-hydroxy-3-nitrophenyl acetyl (NP) hapten. The present study describes two distinct T cell populations which interact to generate antigen-specific Ts 3. Fractionation of the T cell populations with monoclonal antibody to the L3T4 determinant led to the identification of an NP-specific L3T4 − Ts 3 progenitor population and an L3T4 + helper/ inducer subset. In the presence of NP-coupled antigen, the L3T4 + subset could induce progenitor Ts 3 to differentiate into mature Ts 3 cells. The activity of the L3T4 + inducer population could be replaced with specifically activated cloned helper cells which were not NP-reactive since an I-A b-restricted, insulin-reactive, L3T4 + clone was capable of supporting the generation of NP-specific Ts 3. Inducer activity appeared to be confined to the T h1 but not the T h2 subset. In addition, 18-hr supernatants from antigen-activated clones were capable of substituting for L3T4 + cells or T cell clones in Ts 3 induction cultures. The Ts maturation/differentiation factor(s) active in these supernatants does not appear to be IL-1, IL-2, IL-3, or interferon-γ alone since purified sources of these lymphokines failed to induce Ts 3 activity.

Antigen-specific immune-suppressor factor in herpes simplex virus type 2 infections of UV B-irradiated mice

UV B-irradiation (280 to 320 nm) of mice at the site of cutaneous infection with herpes simplex virus type 2 (HSV-2) induced suppressor T-cell circuits that decreased HSV-2-induced proliferative responses of HSV-2-immune lymph node cells. Adoptive transfer experiments indicated that splenocytes from UV B-irradiated HSV-2-infected animals contain L3T4+ cells that suppress proliferative responses in vivo, consistent with suppressor inducer cells. However, following in vitro culture of the splenocytes with HSV-2 antigen, the proliferation of immune lymph node cells was inhibited by Lyt2+ suppressor T cells, consistent with antigen-induced suppressor effector cells. Antigen-specific and nonspecific suppressor factors were fractionated from supernatants of HSV-2-stimulated spleen cells by molecular-sieve chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the Sephadex fraction that contained the antigen-specific suppressor factor, in the presence or absence of 2-mercaptoethanol, defined a 115-kilodalton protein consisting of two disulfide-bound components with molecular sizes of 70 and 52 kilodaltons. The implications of these results with respect to the regulation of HSV-induced cell-mediated immunity following UV B-irradiation are discussed.

Identification of suppressor T cells in virgin non-responder spleen cells responsible for primary unresponsiveness to L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT).

T cell subsets that regulate antibody responses to L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) in mice that are Ir gene non-responders have been further characterized. We previously defined several T cell subsets in GAT-primed non-responder mice. The Lyt-2+ suppressor-effector T cells suppress responses to GAT and GAT complexed to methylated BSA (GAT-MBSA). The Lyt-1+ cell population is complex and can be separated into I-J- Th cells, which support responses to GAT and GAT-MBSA. After priming, the Lyt-1+, I-J+ cell population contains suppressor-inducer cells that activate precursors of suppressor-effector cells to suppress responses to GAT and GAT-MBSA as well as Ts cells that directly inhibit responses to GAT but not GAT-MBSA. By contrast, the Lyt-1+ cells from virgin mice contain only cells that directly suppress responses to GAT but not GAT-MBSA. The major question addressed in the present studies was whether the Lyt-1+, I-J+ Ts cells in virgin and primed mice and the suppressor-inducer cells in GAT-primed mice were functionally and serologically distinct subsets. The studies used mAb and panning procedures to separate cell populations and inhibition of PFC cell responses to functionally define the activity of the cell populations. We used the following two mAb that were raised by immunizing rats with GAT-specific suppressor factors: 1248A4.10 (known to react with suppressor-inducer cells) and 1248A4.3, another reagent from the same fusion. Lyt-1+ cells from virgin spleens contained Ts cells that were A4.10-, A4.3+ and no suppressor-inducer T cells, whereas Lyt-1+ cells from GAT-primed spleens contained Ts cells that were A4.10-, A4.3+ as well as A4.10+, A4.3- suppressor-inducer cells. Thus, the Lyt1+, I-J+ cell subset can be divided into two functionally and serologically distinct subsets, direct Ts cells (1248A4.3+), which suppress responses to GAT but not GAT-MBSA, and GAT-primed suppressor-inducer T cells (1248A4.10+).

Defective Helper Function of Purified T4 Cells and Excessive Suppressor Activity of Purified T8 Cells in Patients With B-Cell Chronic Lymphocytic Leukemia. T4 Suppressor Effector Cells Are Present in Certain Patients

We investigated helper and suppressor functions to B-cell responses and T-T cell interactions of purified T4 and T8 cells from 20 untreated patients with B-cell chronic lymphocytic leukemia (CLL). Appropriate mixtures of purified T4 or T8 cells from patients with CLL were cultured with purified B cells or T4 and B cells from normal donors for 7 days with pokeweed mitogen (PWM). IgM, IgA, and IgG produced were determined in the supernatants of these cultures by a heavy chain-specific enzyme-linked immunosorbent assay (ELISA) and compared to those obtained by the corresponding mixtures of T4, T8, and B cells from normal donors. Purified T4 cells from 14 of 20 patients with CLL exhibited defective helper function (P less than .001) to immunoglobulin (Ig) production by purified B cells from normal donors. Purified T4 cells from 6 of these 14 patients were able to suppress significantly (P less than .001) and in a concentration-dependent manner Ig production by mixtures of T4 and B cells from normal donors, in the absence of T8 cells. These suppressor effector T4 cells from certain patients were partially radiosensitive. Purified T8 cells from 8 of 20 patients with CLL exhibited excessive suppressor activity. These cells significantly suppressed (P less than .001), Ig production by mixtures of T4 and B cells from normal donors to a degree significantly higher (P less than .005) than that observed by equal numbers of T8 cells from normal donors. This inhibition was dependent on the numbers of the T8 CLL cells added to the cultures. Excessive suppressor activity by T8 CLL cells was at least in part radiosensitive in four of eight patients. These results demonstrate a wide range of immunoregulatory T-cell abnormalities in patients with CLL. Naturally occurring T4 suppressor effector cells, directly inhibiting Ig production by mixtures of T4 and B cells, in the absence of T8 cells, are present in certain patients with CLL.

Defective helper function of purified T4 cells and excessive suppressor activity of purified T8 cells in patients with B-cell chronic lymphocytic leukemia. T4 suppressor effector cells are present in certain patients

We investigated helper and suppressor functions to B-cell responses and T-T cell interactions of purified T4 and T8 cells from 20 untreated patients with B-cell chronic lymphocytic leukemia (CLL). Appropriate mixtures of purified T4 or T8 cells from patients with CLL were cultured with purified B cells or T4 and B cells from normal donors for 7 days with pokeweed mitogen (PWM). IgM, IgA, and IgG produced were determined in the supernatants of these cultures by a heavy chain- specific enzyme-linked immunosorbent assay (ELISA) and compared to those obtained by the corresponding mixtures of T4, T8, and B cells from normal donors. Purified T4 cells from 14 of 20 patients with CLL exhibited defective helper function (P less than .001) to immunoglobulin (Ig) production by purified B cells from normal donors. Purified T4 cells from 6 of these 14 patients were able to suppress significantly (P less than .001) and in a concentration-dependent manner Ig production by mixtures of T4 and B cells from normal donors, in the absence of T8 cells. These suppressor effector T4 cells from certain patients were partially radiosensitive. Purified T8 cells from 8 of 20 patients with CLL exhibited excessive suppressor activity. These cells significantly suppressed (P less than .001), Ig production by mixtures of T4 and B cells from normal donors to a degree significantly higher (P less than .005) than that observed by equal numbers of T8 cells from normal donors. This inhibition was dependent on the numbers of the T8 CLL cells added to the cultures. Excessive suppressor activity by T8 CLL cells was at least in part radiosensitive in four of eight patients. These results demonstrate a wide range of immunoregulatory T-cell abnormalities in patients with CLL. Naturally occurring T4 suppressor effector cells, directly inhibiting Ig production by mixtures of T4 and B cells, in the absence of T8 cells, are present in certain patients with CLL.

Trypanosoma cruzi-induced suppression of IL-2 production. II. Evidence for a role for suppressor cells.

Suppression of IL-2 production during experimental Chagas' disease accounts at least in part for the overall depressed state of the immune system in infected mice. The failure to produce IL-2 in response to mitogen stimulation is not the result of the lack of cells capable of producing IL-2, but appears to be due to regulation of IL-2 production by suppressor cells. This conclusion is supported by cell-mixing experiments where the ability of cells from infected mice to suppress normal spleen cell IL-2 production is evident. Although depletion of plastic and Sephadex G-10 adherent cells results in modest increases in IL-2 production by spleen cells from infected mice, even in the presence of normal adherent cells as a source of IL-1 producers, IL-2 production does not approach normal levels. Also, isolated macrophages are not by themselves suppressive for normal spleen cell IL-2 production, whereas plastic and G-10 nonadherent cells from infected mice are. Depletion of Thy-1+ and Ly-2+ cells not only completely abrogates the ability of spleen cells from infected mice to suppress normal IL-2 production, but results in a cell preparation which actually enhances IL-2 production. Anti-Ly-2 and C treatment of infected spleen cells also markedly enhances their ability to produce IL-2. These results indicate a major role for Ts cells in the regulation of IL-2 production, and a relatively minor role of macrophages as direct effector cells of suppression in this response. The ability to enhance IL-2 production in this system with PG synthesis inhibitors suggests a role for PG-producing cells such as macrophages in the suppressor mechanism, perhaps as inducers of the suppressor effector cells.

A novel epitope of the LFA-1 antigen which can distinguish killer effector and suppressor cells in human CD8 cells

The CD4 subset of cells displays helper/inducer activity and recognizes class II antigens of the major histocompatibility complex (MHC), while the CD8 subset recognizes class I MHC antigens and exhibits cytotoxic or suppressor function. Considerable functional as well as corresponding phenotypic heterogeneity exists within the two major T cell subsets. Although the CD8+ population contains pre-cytotoxic, cytotoxic, pre-suppressor and suppressor effector T cells, these distinctions still rest largely on the use of functional assays. Attempts have been made to define the CD8+ precursor of the killer cell with new monoclonal antibodies. But more precise phenotypic distinctions between the functional subpopulations within CD8+ cells will be needed. We have now developed a monoclonal antibody, anti-S6F1 which can distinguish killer effector and suppressor effector cells in CD8 lymphocyte populations. The cell-surface structure defined by this antibody comprises two glycoproteins with relative molecular mass (Mr) 180K and 95K respectively. Also sequential immunoprecipitation studies and two dimensional gel electrophoresis indicate that anti-S6F1 recognizes a novel epitope on the LFA-1 antigen.

Effect of antigen priming on T-cell suppression: I. Activity of Ly 1 +2 + feedback suppressor T-cell precursors after isolation from competing Ly 2 − T cells

Previous experiments have demonstrated that feedback suppression of murine antibody responses occurs in vitro after exposure of unprimed T-cell subsets to suppression-inducing signals from primed cells, resulting in suppression of primary and secondary IgM as well as IgG anti-SRBC responses. However, following priming with antigen when cells appear which are capable of inducing feedback suppression, the ability of unfractionated splenic T-cell populations to mediate detectable feedback suppression in vitro rapidly disappears, suggesting that priming alters the expression of feedback suppression at the same time as providing for its induction. In the present study, we have succeeded in isolating active feedback suppressor T-cell precursors (preTs) in the Ly 1 +2 + and L3T4 − T-cell populations from SRBC-primed as well as from unprimed mice, demonstrating that preTs are not lost after priming. The preTs isolated from primed mice resemble those isolated from unprimed mice in Ly and L3T4 phenotype, cell dose requirements, kinetics, level of suppression, and requirement for in vitro activation by primed cells. These results imply that antigen priming neither significantly depresses nor enhances the ability of Ly 1 +2 + preTs to participate in feedback suppression and that activated suppressor effector cells are not detectable in the Ly 1 +2 + splenic T-cell subset. Priming does, however, induce an enhancing activity in Ly 2 −, L3T4 + T cells which appears to compete with feedback suppression and thus may account for the absence of detectable feedback suppression when unfractionated T cells from primed mice are the only source of preTs.

Sequential effects of prostaglandins and interferon-gamma on differentiation of CD8+ suppressor cells.

We have previously demonstrated that differentiation of CD8+ Tp44- suppressor cells in pokeweed mitogen (PWM)-stimulated cultures requires soluble factors elaborated by CD4+ cells and monocytes, and that the monocyte signal for such differentiation can be replaced by prostaglandin E2 (PGE2). In this study, we explored the ability of interleukin 2 (IL 2) and interferon-gamma (IFN-gamma) to replace the CD4+ signal. When IL 2 or IFN-gamma was used at concentrations equivalent to those present in supernatants of PWM-pulsed cultures of CD4+ cells, no effect on differentiation of CD8+ cells was observed. However, a potent suppressor inducing activity was detected when IFN-gamma, but not IL 2, was mixed with supernatants derived from cultures of PWM-pulsed purified monocytes (M phi sup) or with 10(-8) M PGE2. Differentiated CD8+ suppressor cells (Ts) inhibited both PWM-stimulated proliferative response of CD4+ cells and immunoglobulin production by B cells. The signals mediated by the M phi sup or PGE2 and IFN-gamma were shown to act sequentially. That is, M phi sup or PGE2 was required initially, followed by an IFN-gamma-dependent differentiative step. These studies thus suggest a cascade of cellular interactions involving monocytes, CD4+ cells, and CD8+ Ts precursors that are required for the differentiation of CD8+ suppressor effector cells.

Phenotypic identification of suppressor-effector, suppressor-amplifier and suppressor-inducer T cells of B cell differentiation in man.

Using monoclonal anti-Leu8 antibody to isolate subpopulations of human helper/inducer (CD4+) and suppressor/cytotoxic (CD8+) T cells, we have investigated the role of these subpopulations in the regulation of B cell differentiation in the human autologous mixed leukocyte reaction (AMLR). Whereas AMLR-activated CD8+,Leu8- cells were capable of suppressing fresh AMLR cultures in the absence of fresh CD8+ cells, CD8+,Leu8+ cells suppressed only those cultures containing fresh CD8+ cells. On the other hand, CD8+,Leu8- cells became suppressor cells only when cultured in the presence of CD8+,Leu8+ cells. Finally, the development of CD8+ suppressor cells was dependent on the presence of CD4+,Leu8+ cells; CD4+,Leu8- cells were incapable of acting as suppressor-inducer cells, but have been shown previously to mediate T cell help for B cell differentiation. Thus, at least 3 phenotypically distinct subsets of T cells interact sequentially to generate suppression of B cell differentiation induced in the AMLR: CD4+,Leu8+ suppressor/inducer cells, CD8+,Leu8+ suppressor-amplifier cells and CD8+,Leu8- suppressor-effector cells.

The human immunoregulatory T cell circuit: Recent progress and its clinical implications.

The present studies indicate that both the heterogeneity and functional programs of human T lymphocytes can be distinguished. Within the T4 subset, which is responsible for inducer/helper functions in T-T, T-B and T-macrophage interactions, discrete subpopulations are present; T4 cells bearing the 2H4 molecule (T4+2H4+) induce T8+suppressor effector cells, and T4 cells bearing the 4B4 molecule (T4+4B4+) induce help for B cell Ig synthesis. Within the T8 subset are precursors and effector cells responsible for both suppressor or cytotoxic function. It is now evident that T4 cells show a preferential interaction with class II MHC determinants on accessory or target cells, whereas T8 cells have a preference for class I determinants. Furthermore, the T4 and T8 glyco-proteins themselves may function as associative recognition structures in such functions. Recent work has elucidated the role of the T3-Ti antigen receptor complex which is involved in both antigen recognition and T cell activation. The T3 molecule, a nonpolymorphic determinant is membrane-associated with the 90 KD Ti heterodimer, a highly polymorphic structure with both constant and variable regions, making up the T cell receptor for antigen. It is believed that these unique cell surface glycoproteins will have a critical role in regulating the nature and intensity of the immune response. The clinical relevance of these cell surface glycoproteins in human diseases also will be discussed.

Human suppressor T cells: Induction, differentiation, and regulatory functions

T-cell-mediated suppression of human immune responses involves a complex interaction between distinct lymphocyte subsets with suppressor-inducer and suppressor-effector functions. Recent studies with subset-specific monoclonal antibodies have defined a characteristic phenotype of suppressor-inducer cells (CD4 + Leu8 + 2H4 + 4B4 −) that can be distinguished from that of helper cells for antibody synthesis (CD4 + Leu8 − 2H4 − 4B4 +). Similarly, suppressor-effector cells (CD8 + CD11 + Tp44 − can typically be defined as a subset separable from cytotoxic T cells (CD8 + CD11 − Tp44 +). Both antigen-specific and nonspecific interactions are important in suppressor T-cell activation and function. Soluble signals required for differentiation of CD8 + suppressor cells include an indomethacin-sensitive monocyte product and interferon gamma. In contrast, proliferation of the CD8 + suppressor cell subset depends on stimulations first by a product of CD4 + Leu8 + cells, T suppressor cell growth factor, and second by interleukin 2. Although the molecular basis of antigen-specific interactions between CD4 + and CD8 + cells in suppressor cell generation has not been defined, it may involve both conventional, presumably MHC-restricted, interactions between antigen and antigen receptors, as well as anti-idiotypic interactions of suppressor-effectors with determinants on suppressor-inducer receptors. Progress in elucidating requirements for activation, growth, and differentiation of suppressor cells should facilitate long-term culture of such cells and lead to clearer understanding of mechanism of suppressor-cell mediated immunoregulation.

Nonspecific T suppressor factor (nsTsF) cascade in contact sensitivity: nsTsF-1 causes an Ly-1+2- I-A+ immune T cell to produce a second, genetically restricted, nsTsF-2.

We studied the mode of action of the nonspecific T suppressor factor (nsTsF-1) made in the picryl (TNP) system when T acceptor cells armed with antigen-specific TsF are triggered by antigen in the context of I-J. This suppressor factor does not inhibit the passive transfer of contact sensitivity directly, as shown by its failure to inhibit passive transfer by immune cells deprived of I-A+ cells. Its immediate target is an immune, antigen-specific, Ly-1+2-, I-A+ T cell. This cell, which may be regarded as a T suppressor effector cell (Ts-eff-2), produces nsTsF-2 when exposed sequentially to nsTsF-1 and antigen. This nsTsF subsequently inhibits the passive transfer of contact sensitivity. The action of nsTsF-2 is MHC genetically restricted. As the nsTsF-2 bears I-A determinant(s), this raises the possibility that it may act by combining with the recognition site for I-A on the T cell that mediates contact sensitivity.

Direct Demonstration of Immunoregulatory T‐Cell Defects in Patients with Systemic Lupus Erythematosus

The present study was undertaken to determine directly whether immunoregulatory T cells have a defective suppressor function in patients with systemic lupus erythematosus (SLE), and whether anti-T-cell antibodies are essential for immunoregulatory T-cell defects. Peripheral blood T cells and T-cell subsets were determined in 52 SLE patients. The ratio of T4 to T8 cells was distributed over a wider range in patients with SLE than in the controls. Patients with SLE were divided into three groups (low, normal and high) by the T4/T8 ratio. Lymphocytes from 12 SLE patients (7 with low and 5 with high T4/T8 ratios) were studied extensively. Their disease was inactive or in remission. Anti-T-cell antibodies were not detected, and yet the patients had immunological abnormalities characterized by the presence of antinuclear antibodies and hypergammaglobulinaemia. The SLE patients with high T4/T8 ratios had a decreased number of T8 cells, and defective suppressor-effector cells. In contrast, patients with low T4/T8 ratios had decreased T4 cells and/or increased T8 cells, and defective suppressor-inducer cells. Two patients with low T4/T8 ratios had both suppressor-effector and suppressor-inducer cell defects. These results indicate that immunoregulatory circuits in SLE patients are heterogeneous and that immunoregulatory defects exist even when the disease is inactive or in remission. Anti-T-cell antibodies were not essential for such immunoregulatory defects. Thus, immunoregulatory T-cell defects and the development of SLE may be independent conditions due to other unknown causes.

Regulation of immune responses by T cell subsets. Role of helper and suppressor T cells in the development and expression of MHC-restricted antibody responses to L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) by (responder X responder)F1 spleen cells.

The roles of helper and suppressor T cells in the development and expression of antibody responses to GAT were studied in (responder X responder)F1 mice immunized with parental GAT-M phi. Spleen cells from (B10 X B10.D2)F1 mice primed in vivo with B10 or B10.D2 GAT-M phi developed secondary in vitro plaque-forming cell (PFC) responses only when stimulated by GAT-M phi syngeneic with the GAT-M phi used for in vivo priming. By contrast, virgin F1 spleen cells developed comparable primary PFC responses to both parental GAT-M phi Co-culture of T cells from (B10 X B10.D2)F1 mice primed in vivo by B10 GAT-M phi with virgin (B10 X B10.D2)F1 spleen cells demonstrated the presence of suppressor cells that inhibited the primary response of virgin spleen cells stimulated by B10.D2 GAT-M phi. Spleen cells from (B10 X B10.D2)F1 mice primed in vivo with B10.D2 GAT-M phi had suppressor T cells that suppressed primary responses stimulated by B10 GAT-M phi. The suppressor T cell mechanism was composed of at least two regulatory T cell subsets. Suppressor-inducer T cells were Lyt-2-, I-J+ and must be derived from immune spleen cells. Suppressor-effector T cells can be derived from virgin or immune spleens and were Lyt-2+ cells. When the suppressor mechanism was disabled by treatment with 1000 rad gamma irradiation or removal of Lyt-2+ cells, Lyt-2-helper T cells from (B10 X B10.D2)F1 mice primed with B10 GAT-M phi provided radioresistant help to virgin F1 B cells stimulated by B10 but not B10.D2 GAT-M phi. Suppressor inducer Lyt-2-,I-J+ cells from B10 GAT-M phi-primed (B10 X B10.D2)F1 mice were separated from the primed Lyt-2-,I-J-helper T cells. In the presence of Lyt-2+ suppressor effector cells, the Lyt-2-,I-J+ suppressor-inducer suppressed the primary response of virgin spleen or virgin T plus B cells stimulated by both B10 and B10.D2 GAT-M phi. Therefore, suppressor T cells were able to suppress primary but not secondary GAT-specific PFC responses stimulated by either parental GAT-M phi. These results showed that immunization of (responder X responder)F1 mice with parental GAT-M phi results in the development of antigen-specific helper and suppressor T cells. The primed helper T cells were radioresistant and were genetically restricted to interact with GAT in association with the major histocompatibility complex antigens of the M phi used for in vivo priming.(ABSTRACT TRUNCATED AT 400 WORDS)

Human cord blood suppressor T lymphocytes: I. Phenotype and target of the inducer of suppressor cell factor.

The present study examines the characteristics of the cord suppressor T cells and their targets. When an inducer of suppressor T cell factor (TisF) from culture supernatant of alloantigen-activated cord lymphocytes was used as a source of suppression, adult lymphocyte response to soluble antigen candidin, alloantigens, and pokeweed mitogen were all suppressed. These results suggest that TisF acts primarily on T cells in an antigen-nonspecific fashion. Furthermore, preculture T cell irradiation, but not T8+ cell depletion, of adult lymphocytes abrogated the suppressive effect of TisF on the PWM-stimulated IgG production, suggesting that the target of TisF belongs to the radiosensitive T8-(T4+) T cell subset. When different cord T cell subsets were tested for suppressor activity, only radiosensitive T4+ cells were capable of suppressing IgG production by adult lymphocytes. Neither preculture T8+ cell depletion nor irradiation of adult T cells affected the suppression. Taken together, these results suggest that the suppressor activity of cord T cells originated from an inducer of suppressor cells that activates radiosensitive T4+ suppressor effector cells through TisF. In turn, these effector cells act on either radioresistant T4+ helper T cells or B cells or both.

A burn induced Ly-2 suppressor T cell lowers resistance to bacterial infection

Suppressor T cell activity after major burn injury in a murine model has been well characterized. Suppressor cells have also been demonstrated in patients after major burn, and suppressor cell activity has been temporally correlated with septic episodes. A splenic Ly-2 T suppressor effector (Tse) cell appearing 7 days after a 30% full thickness burn has been identified in a murine model. A rat monoclonal antibody (14-8c3-12) directed against a factor produced by the Tse cell (Tsef) can enhance depressed in vitro mixed lymphocyte reaction (MLR) responses of Day 7 burn spleen cells without enhancing control spleen cell activity. Additionally, 14-8c3-12 can block the suppressive effect of these burn T cells on normal T cells. A cecal ligation and puncture (CLP) model using a 25-gauge needle (LD 15) was used to assess the contribution of burn T cells to post-CLP mortality. Normal spleen cells injected into syngeneic recipients followed by CLP did not affect mortality (13%). Burn spleen cells injected into normal recipients enhanced mortality sixfold (90%) after CLP. The effect could be reversed by removing Ly-2 T cells (30% mortality) but not Ly-I T cells (100% mortality) prior to cell transfer. Simultaneous injection of 14-8c3-12 antibody with burn T cells reduced mortality after CLP significantly (20%). Injection of 14-8c3-12 did not improve survival after CLP in control animals not injected with burn T cells (20%). Ly-2 T suppressor effector cells found in the spleens of mice 7 days postburn enhance the lethality of a purely bacterial septic challenge. A monoclonal antibody to the Tsef can reverse this effect in vivo.