HLA-linked nonresponsiveness to Cryptomeria japonica pollen antigen. I. Nonresponsiveness is mediated by antigen-specific suppressor T cell

The objective of this study was to elucidate the cellular mechanism of IgE nonresponse to the Cryptomeria japonica (Japanese cedar) pollen antigen (CPAg), which was shown in our previous study to be HLA-linked (1). We established an assay system for the measurement of small amounts of anti-CPAg IgE antibody, both in an antigen-specific and isotype-specific manner, and a culture system to induce antigen-driven IgE antibody synthesis in vitro. By using these methods, we clarified that the function of the HLA-DR molecule in the CPAg-driven IgE response is similar to that of I-A or I-E molecule in mice, namely the product of immune response genes (Ir-genes), because anti-HLA-DR monoclonal antibody blocked the response, and the interaction between monocyte and monocyte-depleted peripheral blood lymphocytes (PBL) to respond to CPAg was restricted by HLA-DR. Furthermore, PBL from nonresponders revealed a specific IgE response to CPAg when the Leu-2+3- T cell fraction was depleted, thereby suggesting that even nonresponders have Leu-2-3+ T cell and B cell clones specific for CPAg, and they apparently show no response due to the presence of CPAg-specific Leu-2+3- suppressor T cells. This suppressor T cell fraction abolished the IgE response of the autologous B + monocyte + Leu-2-3+ T cell in a CPAg-specific manner. The current cellular analysis together with our previous genetic analysis strongly suggest that the HLA-linked IgE nonresponse to CPAg is mediated by CPAg-specific suppressor T cells. The HLA-linked gene controlling the nonresponsiveness to CPAg is thus designated as the immune suppression gene for CPAg (Is-CPAg). Mapping of Is-CPAg within HLA-DQ subregion is discussed.     

Surface markers on the T cells that regulate cytotoxic T-cell responses I. The Ly phenotype of suppressor T cells changes as a function of time, and is distinct from that of helper or cytotoxic T cells

Regulatory T cells can be obtained from primary mixed lymphocyte cultures of CBA spleen cells responding to BALB/c stimulators. At day 3 of culture, T cells are generated which can either help or suppress the generation of cytotoxic T cells in a second primary MLC culture. The regulatory activity observed depends on the conditions employed in the assay system allowing independent assay of different functional cell types which coexist in the cultures. Both the helper activity and the suppressor activity are mediated by differentiated antigen-specific T cells whose function is radioresistant. The Ly phenotype of these regulatory cells was tested. At day 3 of the first-step culture, the phenotype of the helper cells is Ly 1.1+ Ly 2.1-, whereas the inhibitory cells are Ly 1.1 Ly 2.1+. At day 5 of M LC culture, suppressor activity and helper activity are also observed. However, at this point, a suppressor cell which is Ly 1.1-Ly 2.1+ represents the major inhibitory activity. It is not clear whether this change in suppressor cell phenotype as a function of time in culture represents one differentiation pathway or cells derived from two different precursor cells. The Ly phenotype of helper or cytotoxic T cells did not change as a function of time in culture. In day 5 first-step cells, the cytotoxic cells were typed as Ly 1.1+ 2.1+, whereas the inhibitory cells present in aliquots of the same treated cell population expressed the Ly 1.1- Ly 2.1 phenotype. Taken together, these observations show that the antigen-specific suppressor cells and helper cells which regulate the generation of cytotoxicity, and the cytotoxic cells themselves represent physically distinct subclasses of T cells.     

Immune regulation by platelet-activating factor. I. Induction of suppressor cell activity in human monocytes and CD8+ T cells and of helper cell activity in CD4+ T cells

Platelet-activating factor (PAF) is a powerful mediator of inflammation. We have recently described a potential role for PAF in immune reactions, as it inhibits T cell proliferation and IL-2 production in response to mitogens. To further define the mechanism through which this inhibition is exerted, we used a coculture system in which PBML are preincubated with increasing concentrations of PAF for 24 h, followed by washing, treatment with mitomycin C and addition to fresh autologous PBML stimulated with PHA. In this context, a significant (40 to 60%) inhibition of proliferation was observed. In parallel, PAF-pre-treated cells induced a reduction (30 to 50%) of IL-2 production by PHA-stimulated lymphocytes. The PAF receptor antagonist BN52021 could partially block the PAF-induced suppressor cell activity, but also showed some suppressor cell-inducing properties of its own (20 to 30%). The expression of suppressor cell function during the co-culture could be partially abrogated by the inclusion of indomethacin, suggesting that cycloxygenase metabolites of arachidonic acid were involved in this phase of suppression. When PBML were fractionated into monocytes, lymphocytes, or T cell subsets before pre-incubation with PAF, indomethacin-sensitive suppressor cell function was generated in the monocyte population. Monocyte-depleted lymphocytes showed slight helper effect, whereas CD8+ T cells were induced to become indomethacin-resistant suppressor cells. CD4+ T cells, in contrast, were activated to exert very marked helper effect. When incubated with PAF for 24 h, monocyte-depleted lymphocytes showed a 30% decrease in CD4+ T cell numbers and a 50% increase in CD8+ T cell numbers. Our data suggest a novel immunoregulatory role for PAF and potentially important interactions of this lipid mediator of inflammation with lymphocyte and monocyte functions.     

Cellular mechanisms in the in vitro inhibition of pokeweed mitogen-induced B cell differentiation by immunoglobulin for intravenous use

Polyspecific monomeric IgG for i.v. use (IgSRK; Sandoglobulin) can inhibit in vitro pokeweed mitogen (PWM)-induced B cell differentiation. This antigen-nonspecific inhibition is an early event, because removal of the IgSRK from cultures of PWM-stimulated peripheral blood mononuclear cells (PBMC) after as short a period as 24 hr could not reverse the inhibitory effects. Furthermore, replacement of the IgSRK-exposed T cells after 48 hr of culture with fresh autologous T cells could not abrogate the inhibition. In addition, IgSRK exerted an inhibitory effect on non-T cells even before their activation by PWM. Neither augmentation of T suppressor activity nor inhibition of T helper activity could be demonstrated as a consequence of interaction with IgSRK. Irradiation of the T cells before culture, supplementing the culture medium with exogenous interleukin 2, monocyte depletion, or depletion of the Leu-11+ population had no effect on the IgSRK-mediated inhibition. Tonsil cells were as susceptible to the inhibitory effects of IgSRK as were unseparated PBMC. Taken together, these experiments point to a direct inhibitory effect of IgSRK on the B cell in this antigen-nonspecific system. However, minor roles for monocytes, T cells, and/or Leu-11+ cells cannot be excluded. This inhibitory capacity of IgSRK might be efficacious clinically in the treatment of autoimmune disorders in which pathogenic autoantibodies play a role. However, such treatment might also inhibit desired antibody responses to vaccinations and/or infectious agents.     

Suppression of lymphoproliferation by high concentrations of normal human mononuclear leukocytes.

Mononuclear leukocytes (MNL) include cells that suppress lymphoproliferation in unstimulated and antigen-stimulated cultures. Suppression is demonstrated by increasing the concentration of cells added to cultures and does not require preactivation of suppressor cells. Suprression of 3H-thymidine incorporation occurred if the high concentrations of MNL were added to cultures before the proliferative responses commenced. This suppressive effect of high cell concentration upon 3H-thymidine incorporation is removed by depleting MNL present in high numbers of cells that adhere to foreign surfaces or by preincubating these cells with cycloheximide, puromycin, or pactamycin. The suppressor cell, which only functions when present in a viable state, is radioresistant, adheres to foreign surfaces, remains active through 5 days in culture, and equates with the presence of a cell that is rich in cytoplasmic esterase. The suppressor cell may be of the monocyte series and did not appear to belong to either the T or the B lymphocyte series. This study provides additional evidence that normal immune reactivity in man is under regulatory control. The suppressor mechanism identified herein with normal human MNL is probably related to a similar type of suppression (but at a much lower cell concentration) that has been described with Hodgkin's disease and solid tumors.     

Cooperation between an anti-T cell (anti-CD28) monoclonal antibody and monocyte-produced IL-6 in the induction of T cell responsiveness to IL-2

CD28 is an Ag of 44-kDa Mr that is expressed on the membrane of the majority of human T cells and that is recognized by mAb 9.3. The functional effects of mAb 9.3 on peripheral blood T cells were studied. mAb 9.3 was not mitogenic, unless it was combined with PMA. When CD28 was cross-linked after binding of mAb 9.3 to the T cell by immobilized or soluble anti-mouse IgG, T cells proliferated in response to rIL-2, provided that monocytes were also present. The additional signal required for IL-2 responsiveness after cross-linking of CD28 could also be delivered in cultures of purified T cells by a cellfree monocyte culture supernatant. Expression of IL-2R on about 10% of the T cells was demonstrated by staining with an anti-IL-2R mAb, and was found to be largely restricted to CD4+ cells. The active compound responsible for the helper signal in the monocyte culture supernatant was identified as IL-6 because purified IL-6 (but not IL-1 beta) had similar activity and because an antiserum to IL-6 (but not an antiserum to IL-1 beta) neutralized the activity of the monocyte supernatant and blocked T cell proliferation. An anti-IL-2R antibody also completely inhibited T cell proliferation induced by the combination of mAb 9.3, IL-2, and IL-6. Our results provide evidence that cross-linking of CD28 induces functional IL-2R and that this activity is dependent on a helper signal provided by monocytes, more specifically IL-6. Moreover, our results indicate that IL-6 (previously called B cell stimulatory factor-2) is active on T cells. If a natural ligand for CD28 can be identified, the mechanism of induction of IL-2 responsiveness described here might explain how T cells become nonspecifically involved in an ongoing cellular immune reaction.     

Suppressor cells in the effector phase of autologous cytotoxic reactions in cancer patients

Summary Cytotoxicity was induced in lymphocytes (CL) from 10 out of 15 patients by autologous mixed lymphocyte tumor cell culture and further cultivation with recombinant interleukin-2. In cells from 3 of the 10 patients, cytotoxicity was suppressed by more than 50% when autologous peripheral blood mononuclear cells (PBMC) from the patients with large tumors were added to the autologous killing system. The cells responsible for suppressing the cytotoxicity in the effector phase were adherent or nonadherent to plastic depending on the patient examined. The T cell fraction from 1 patient significantly suppressed the cytotoxic activity, and this suppression was seen only in the autologous system. On the other hand, plastic adherent cells but not T cells from PBMC of 2 subjects suppressed the cytotoxic activity of CL. The reason why the main cell population suppressing the CL activity differed among the patients is unclear. However, the findings that the suppression was mostly abrogated following resection of the tumor mass suggested that suppressor cells, either of macrophage lineage or T cells, are induced in patients with a large tumor mass. This speculation is supported by the finding that the PBMC from a patient with tumor recurrence regained the suppressive activity.     

Surface markers on the T cells that regulate cytotoxic T-cell responses

Regulatory T cells can be obtained from primary mixed lymphocyte cultures of CBA spleen cells responding to BALB/c stimulators. At day 3 of culture, T cells are generated which can either help or suppress the generation of cytotoxic T cells in a second primary MLC culture. The regulatory activity observed depends on the conditions employed in the assay system allowing independent assay of different functional cell types which coexist in the cultures. Both the helper activity and the suppressor activity are mediated by differentiated antigen-specific T cells whose function is radioresistant. The Ly phenotype of these regulatory cells was tested. At day 3 of the first-step culture, the phenotype of the helper cells is Ly 1.1⁺ Ly 2.1^–, whereas the inhibitory cells are Ly 1.1⁺ Ly 2.1⁺. At day 5 of MLC culture, suppressor activity and helper activity are also observed. However, at this point, a suppressor cell which is Ly 1.1^– Ly 2.1⁺ represents the major inhibitory activity. It is not clear whether this change in suppressor cell phenotype as a function of time in culture represents one differentiation pathway or cells derived from two different precursor cells. The Ly phenotype of helper or cytotoxic T cells did not change as a function of time in culture. In day 5 first-step cells, the cytotoxic cells were typed as Ly 1.1⁺ 2.1⁺, whereas the inhibitory cells present in aliquots of the same treated cell population expressed the Ly 1.1^– Ly 2.1⁺ phenotype. Taken together, these observations show that the antigen-specific suppressor cells and helper cells which regulate the generation of cytotoxicity, and the cytotoxic cells themselves represent physically distinct subclasses of T cells.     

Detection of the dominant expression of the TEPC-15 idiotypic determinant(s) on phosphorylcholine-specific suppressor T lymphocytes in vitro

Phosphorylcholine-(PC) specific suppressor T lymphocytes, induced by immunization with PC-coupled syngeneic spleen cells and capable of suppressing antibody production in an in vitro system, were successfully obtained by removal of a PC-nonspecific, i.e., diazo-phenylstructure-directed, suppressor cell population using an immunoadsorbent column coupling an unrelated hapten with a diazo phenyl structure such as azobenzene arsonate (ABA). Column-purified PC-specific suppressor T cell activity was completely abrogated by treatment of the cells with anti-TEPC-15 (T-15) anti-idiotypic antibody and complement, or by the continuous presence of that antibody in the culture, whereas nonpurified suppressor cell activity was resistant to such treatment. Thus, the column-purified PC-specific suppressor T lymphocytes in BALB/c mice have a very homogeneous T-15 idiotypic determinant(s) on their functional receptors for antigen similar to those present on PC-specific antibody and/or B lymphocytes. Because of these results, we envision the growing importance of analysis of the fine specificity of the idiotype repertoire of T lymphocytes after purification of a hapten-specific population.     

The role of adherent accessory cells in the generation of effector suppressor T cells

The role of accessory cell populations in the generation of effector suppressor (Ts3) cells was studied. By using an in vitro culture system, it was previously determined that the induction of NP-specific effector suppressor activity requires T cells, antigen, and an anti-idiotypic B cell population. We now demonstrate that the generation of Ts3 cells in this system also requires accessory cells. The accessory population appears to play a role in the processing and presentation of antigen. These antigen-presenting accessory cells are required early in the induction phase of Ts3 generation. These accessory cells can present NP coupled to immunogenic or non-immunogenic polypeptide carriers, including polymers of L-amino acids. However, NP coupled to polymers of poorly metabolized D-amino acids fail to induce suppressor T cell generation. Furthermore, the data demonstrate that an H-2 homology must exist between the Ts3 precursors and the antigen-presenting cell population if suppressor activity is to be generated. We also characterize the differential genetic restrictions that govern the induction of Ts3 cells that control suppression of either T cell or B cell responses. The data suggest that although I-J region encoded gene products control the induction and effector phases of suppressor cell activity as measured on T cell responses, the suppression of B cell responses appear to be controlled by I-A gene products. Possible cellular mechanisms that might explain these findings are discussed.     

Acetyl-CoA synthetases ACSS1 and ACSS2 are 4-hydroxytamoxifen responsive factors that promote survival in tamoxifen treated and estrogen deprived cells

Acetyl-CoA synthetases ACSS1 and ACSS2 promote conversion of acetate to acetyl-CoA for use in lipid synthesis, protein acetylation, and energy production. These enzymes are elevated in some cancers and important for cell survival under hypoxia and nutrient stress. 4-hydroxytamoxifen (4-OHT) can induce metabolic changes that increase cancer cell survival. An effect of 4-OHT on expression of ACSS1 or ACSS2 has not been reported. We found ACSS1 and ACSS2 are increased by 4-OHT in estrogen receptor-α positive (ER+) breast cancer cells and 4-OHT resistant derivative cells. ERα knockdown blocked ACSS1 induction by 4-OHT but not ACSS2. 4-OHT also induced ACSS2 but not ACSS1 expression in triple negative breast cancer cells. Long-term estrogen deprivation (LTED) is a model for acquired resistance to aromatase inhibitors. We found LTED cells and tumors express elevated levels of ACSS1 and/or ACSS2 and are especially sensitive to viability loss caused by depletion of ACSS1 and ACSS2 or treatment with an ACSS2-specific inhibitor. ACSS2 inhibitor also increased toxicity in cells treated with 4-OHT. We conclude ACSS1 and ACSS2 are 4-OHT regulated factors important for breast cancer cell survival in 4-OHT-treated and long-term estrogen deprived cells.     

Regulation of myelin basic protein-specific helper T cells in multiple sclerosis: generation of suppressor T cell lines.

Suppressor T cell (Ts) lines specific for myelin basic protein (MBP)-reactive helper T cell (Th) clones were generated from two patients with multiple sclerosis (MS) following a primary culture of peripheral blood mononuclear cells (PBMC) with MBP and cyclosporine A (CsA). These suppressor T cell lines were maintained in culture by alternate stimulation with MBP and antigen-presenting cells (APC). The Ts lines expressed preferentially the CD4 phenotype (5/6 Ts lines tested) and exhibited potent antigen-specific suppressor activity on the proliferation of MBP-specific Th clones and not on the T cell lines with other antigen specificity. For some Ts lines, a Ts-to-Th ratio of 1 was sufficient to inhibit the proliferation of MBP-specific T cells by 90%. The suppressor T cells obtained were weakly responsive to MBP and required the presence of the autologous PBMC for proliferation. Furthermore, proliferation of these suppressor T cell lines was restricted by HLA-DR molecules (for CD4+ Ts lines) and HLA class I (for a CD8+ Ts line). The suppressor T cell lines generated and the techniques described in this study may be helpful in our understanding of the events involved in the immune regulation in MS and other autoimmune diseases.     

Novel mechanisms of specific suppression of anti-hapten antibody response mediated by monoclonal anti-carrier antibody

The cellular mechanisms of the antibody-induced suppression of immune responses were analyzed in the keyhole limpet hemocyanin (KLH) system. Some of the monoclonal anti-KLH antibodies, like KLH-specific suppressor T cell factor (KLH-TsF), were demonstrated to suppress the anti-2,4-dinitrophenyl IgG but not IgM plaque-forming cell responses in a KLH-specific and H-2-restricted manner. The anti-KLH antibodies with suppressive activity reacted with, and in turn, stimulated the suppressor hybridoma (34S-281) with the anti-idiotypic receptor complementary to the idiotypic KLH-TsF of the inducer type. Moreover, because the suppressive activity of the anti-KLH antibody was completely abolished by the treatment of responding spleen cells with anti-Lyt-2 and complement, it was apparent that the suppressive antibody activated suppressor T cell pathways. The isotype or affinity of antibodies is not related to the suppressive activity, because suppressive and nonsuppressive antibodies possess a similar affinity belonging to the same Ig isotypes. It also has been demonstrated that the Fc portion is not the functional site, because the F(ab')2 fragment still has the activity. The antibody specificity is found to be important for determining whether the antibody is suppressive or not. In fact, anti-KLH 26, but not other antibodies without activity, recognizes the particular KLH epitope seen by KLH-TsF, and exclusively interacts with the anti-idiotypic suppressor T cells. Thus, the anti-idiotypic suppressor T cell receives signals both from the suppressive anti-KLH antibody and from KLH-TsF, and transmits the antibody-induced suppressor signals to the effector-suppressor pathway. The size of the repertoire of anti-idiotypic suppressor T cells involved in the suppression seems to be very limited, because only four out of 120 monoclonal anti-KLH antibodies were found to have suppressor activity. The possible mechanisms of the cell interaction mediated by the suppressive antibody are discussed.     

An antigen-specific helper T cell hybridoma produces an antigen-specific suppressor inducer molecule with identical antigenic fine specificity. Implications for the antigen recognition and function of helper and suppressor inducer T cells

We have previously described a T cell hybridoma, A.1.1, that responds to specific Ag (P18, a synthetic polypeptide of defined sequence) in the context of I-Ad by producing lymphokines. Herein we report that this cell also releases, into culture supernatants and ascites fluid, an Ag-specific activity that functions in the induction of suppression of anti-SRBC PFC responses. This suppressive activity requires a) Ag-non-specific accessory molecules from a T suppressor inducer factor, b) Ly-2+ T cells in the assay cultures, and c) the specific Ag (P18) conjugated to the SRBC in the assay cultures. The specificity of the A.1.1-derived activity was demonstrated by the absence of suppression in cultures containing SRBC, BSA-SRBC, or conalbumin-SRBC rather than P18-SRBC. Further, the A.1.1-derived activity bound to, and could be eluted from, P18 but not conalbumin. Using a panel of synthetic variant peptides, we have mapped the critical residues in P18 required for Ag/I-Ad induced activation of A.1.1. These peptides were tested for their ability to act as targets for the A.1.1-derived suppressive activity when conjugated to SRBC and added to assay cultures. All peptides capable of stimulating the A.1.1 T cells to release lymphokines were similarly effective in the suppressor assay. Thus, the recognition of Ag by the T cells and by the T cell-derived activity appeared to be identical. The A.1.1-derived molecule was found to be capable of inducing L3T4- T cells to act as suppressor T cells following culture. These suppressor cells were active in inhibiting anti-SRBC responses in the absence of P18 and bore the Ly-2 surface marker. Thus, it is likely that the function of this Ag-specific molecule is to induce Ly-2+ suppressor T cells and thereby cause the inhibition of the response. This function is distinct from that normally associated with helper T cells and may shed new light on the possible relationship between the cell surface T cell receptor for Ag and Ag-specific T suppressor inducer molecules.     

Suppression of a pokeweed mitogen-stimulated plaque-forming cell response by a human B lymphocyte-derived aggregated IgG-stimulated suppressor factor: suppressive B cell factor (SBF)

The mechanisms whereby formed immune complexes (IC) or immunoglobulin aggregates can suppress further antibody production were explored by culturing normal human peripheral blood mononuclear leukocytes (PBL) with heat-aggregated IgG (HAIgG) and collecting the culture supernatants at 24 hr. These supernatants were found to suppress a pokeweed mitogen (PWM)-induced rheumatoid factor plaque-forming cell (RF-PFC) response in normal individuals. PWM-induced anti-trinitrophenylated sheep red blood cell (TNP-SRBC) PFC were also inhibited by suppressor supernatants from HAIgG-stimulated PBL, suggesting that the polyclonal PFC response was inhibited by a suppressor factor. The suppressor factor inhibited PWM stimulated RF-PFC throughout the culture period, but suppression was maximal at the peak of the RF-PFC response. Suppressor factor was only effective at the initiation of cultures, suggesting that it inhibited early events in the PWM-stimulated RF-PFC response. Molecular weight determination of the suppressor factor by differential membrane fractionation suggested a m.w. range of 30,000 to 50,000, and chromatography on Sephadex G-100 showed a peak activity at an approximate m.w. of 32,000. Studies suggested the factor was not an interferon. Depletion of T lymphocytes by E rosetting and macrophages/monocytes by G-10 adherence did not affect the generation of suppressor factor. Depletion of T lymphocytes (OKT4, OKT8) and NK cells (Leu-11b) by antibody-dependent, complement-mediated cytotoxicity also did not affect the generation of suppressor factor. Depletion of B lymphocytes with OKB7 resulted in the generation of significantly less suppressor factor. Suppression produced by unstimulated purified B lymphocytes was approximately one-half that seen when B lymphocytes were stimulated with HAIgG. Differential membrane fractionation studies suggested that only HAIgG-stimulated B cell cultures contained peak activity in the 30,000 to 50,000 m.w. fraction. Supernatants from unstimulated purified T cells also generated suppression, which was approximately one-half of that seen with HAIgG-stimulated B cells, but no increase in suppressor activity was seen in T cell cultures after incubation with HAIgG. These studies demonstrate that HAIgG is capable of stimulating B lymphocytes to produce a lymphokine, suppressive B cell factor (SBF), which is capable of suppressing a polyclonal PFC response. SBF may be important in feedback control of human immunoglobulin production.     

Control of human B lymphocyte responsiveness: enhanced suppressor T cell activity after in vitro incubation.

Human peripheral blood mononuclear cells (PBM) lost the capacity to generate immunoglobulin-secreting cells (ISC) in response to pokeweed mitogen (PWM) after a period of preincubation in vitro. When fresh PBM were co-cultured with preincubated PBM their response to PWM was inhibited, indicating that enhanced suppressor activity developed in the aged PBM concomitant with the loss of PWM responsiveness. Suppressor cell activity of aged PBM was present within the T lymphocyte population. The suppressor T cell inhibited PWM responsiveness of autologous and homologous PBM to an equivalent degree. The action of the suppressor cell was abrogated by inhibitors of DNA synthesis or by hydrocortisone. A suppressor T cell population with similar characteristics was found in freshly prepared PBM before in vitro incubation. Expansion of this suppressor T cell population during preincubation required cell division. There was no change in the functional capability of the helper T cell population as a result of similar in vitro culture. These observations indicate that a T cell population capable of suppressing PWM-induced generation of ISC can be selectively expanded by in vitro incubation of normal human PBM without additional mitogenic stimulation. Moreover, these data emphasize that control of B lymphocyte differentiation involves a critical interrelationship between T lymphocyte subpopulations exerting both positive and negative influences.     

Immunosuppression during viral oncogenesis. IV. Generation of soluble virus-induced immunologic suppressor molecules

We describe herein functional attributes and generation of immunologic suppressor activity elaborated in response to oncogenic virus infection. Malignant rabbit fibroma virus-induced immunologic suppressor factor (VISF) is a T cell product produced in peak quantities by spleen cells taken from infected rabbits 7 days after infection in vivo. Its production does not appear to require macrophage participation. VISF is highly labile, 3.5 to 12 kDa, and capable of suppressing both B and T lymphocytic responses. Indomethacin and the cyclic nucleotides cAMP and cGMP inhibit its generation. VISF activity is neither antigen nor species specific. It suppresses murine and leporine immune responses to antigens unrelated to the inducing virus. Comparable suppressor activity may be induced by infecting an apparently non-functional rabbit T lymphoma line, RL-5, with malignant rabbit fibroma virus. VISF is principally a suppressor-inducer factor: in vitro, lymphocytes exposed to VISF do not show decreased immunologic responsiveness until 4 days of culture. VISF induces T suppressor cell activity when normal spleen cells are exposed briefly to VISF. Thus, immunosuppressive consequences of malignant fibroma virus infection are partially mediated by a small, non-specific T cell-derived suppressor lymphokine with unique functional characteristics. Non-specific immunologic dysfunction that often attends virus infections may reflect the activity of such factors in humans as well.     

Imbalance of T cell immunoregulatory subsets in primary IgA nephropathy

The peripheral blood distribution of T cell subsets was evaluated in a group of patients with primary IgA nephropathy (IgAN). Results showed that the frequency of helper (CD4+) and suppressor (CD8+) T lymphocytes in IgAN overlapped that seen in healthy blood donors. In addition, the helper T cell subset (CD4+ CDW29+ and CD4+ CD45R+ cells, respectively) proportion was normal, while with particular reference to suppressor T cell subpopulations, a significant decrease of CD8+ CD11+ lymphocytes (the true suppressor cells) was observed in IgAN. These data were further confirmed by the demonstration that monocyte chemotactic responsiveness triggered by lymphocyte-derived chemotactic factor (LDCF), a lymphokine released by CD8+ CD11- cells, was higher in IgAN than in controls. These data suggest that the low frequency of CD8+ CD11+ cells may be responsible for the impaired T cell immunoregulatory activity in patients with IgAN.