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Biomedical subjects

E L Larsson

Publications and source records attributed to E L Larsson.

At least 37 records · Page 2Linked to original sources
PubMed1984

On the role of I-A antigens in lectin- and antigen-induced interleukin 2 production.

The role of I-A molecules in lectin- and antigen-induced interleukin 2 (IL2) production has been analyzed using monoclonal antibodies. Both lectin- and antigen [plus major histocompatibility complex (MHC)]-induced IL2 production were profoundly inhibited by monoclonal anti-I-A antibodies, whereas monoclonal anti-D and anti-K antibodies had no effect. The anti-I-A-mediated inhibition of lectin-induced IL2 production was fully overcome by addition of interleukin 1 (IL 1), while no reconstitution was observed in antigen (plus MHC)-specific induction. Anti-I-A antibodies were also found to inhibit the T cell-independent induction of IL 1 production. I-A antigens appear, therefore, to play two distinct roles in the induction of IL 2 production: (a) I-A molecules are directly involved in mediating activation signals to the macrophages at the level of IL 1 production; (b) I-A epitopes act as restricting elements in specific antigen recognition by T helper cells at the level of IL 2 production, a requirement which is overcome by lectin.

Antibodies, Monoclonal↗
PubMed1984

Activation and growth requirements for cytotoxic and noncytotoxic T lymphocytes.

The number and nature of the "signals" required for lymphocyte activation have been so repetitively and academically discussed over the last 15 years that both the readers and the authors appear exhausted by such exercises. Yet, what may be considered to be the essential question, the basis for self-nonself discrimination, remains to be clarified. Since it has been established that clonal expansion and maturation to effector functions are brought about by polyclonally ("immunologically nonspecific") active factors, it is obvious that the crucial "step" in this context is the initial interaction of antigen with specific receptors of immunocompetent lymphocytes. This initial discriminatory event appears to proceed differently on the various cell subsets. We first deal with the mechanism of induction and growth of cytotoxic-T-lymphocyte precursors, and then discuss the inductive requirements leading to proliferation of T helper cells.

Antigens, Surface↗
PubMed1984

Internal complementarities in the immune system: regulation of the expression of helper T-cell idiotypes.

More than half of BALB/c helper T lymphocytes specific for 2,4,6-trinitrophenyl (TNP)-modified syngeneic spleen cells are inhibited in their proliferative responses to antigen-presenting cells and in their cooperation with B lymphocytes by monoclonal anti-idiotypic antibodies directed to a TNP-binding BALB/c myeloma protein (MOPC 460). This inhibition is specific for anti-TNP-self helper cells of BALB/c origin and is controlled by IgCh-linked genes, as it is not observed with CB.20 helper cells of the same specificity. In contrast, anti-TNP-self helper cells prepared from BALB/c mice that were chronically suppressed with anti-mu chain antibodies and possessed no B lymphocytes were not inhibited by anti-idiotypic antibodies. We conclude that the B-cell antibody repertoires contribute to the selection of the (idiotypic) T-helper-cell repertoires.

Animals↗
PubMed1984

Effects of hydroxyurea on concanavalin-A-induced T-cell proliferation. Depletion of T-cell growth factor-reactive and -producing T lymphocytes.

The effects of eliminating cycling precursors by in vivo administration of high doses of hydroxyurea (HU) in populations of mouse spleen T lymphocytes were studied by membrane immunofluorescence identifying mature Thy 1+, Lyt 2- and Lyt 2+ cell populations and mitogen-induced T-cell growth factor (TCGF) production or reactivity to TCGF. HU treatment results in a sharp decrease in the total number of T cells in mouse spleen, indicating that about 50% of peripheral splenic T lymphocytes have a short survival time in vivo. This depletion is more marked for Lyt 2+ cells than for Lyt 2- cells. The decay of TCGF-reactive spleen cells after drug administration is similar to that of the overall spleen T-cell population. Conversely, production of TCGF induced by concanavalin A is predominantly affected by HU treatment, indicating a shorter life span of the cell(s) involved in TCGF production.

Animals↗
PubMed1983

Induction of cytolytic T lymphocytes by mitogenic lectins is specifically inhibited by anti-Lyt-2 antibodies.

The effects of anti-Lyt-2 antibodies at different levels of lectin-induced cytotoxic T lymphocyte (CTL) responses have been analyzed. Induction of interleukin 2 (T cell growth factor) reactivity ("step 1") by three different lectins was profoundly inhibited by anti-Lyt-2 antibodies. Also lectin-dependent cytotoxicity of polyclonally induced CTL was significantly inhibited by anti-Lyt-2 antibodies, whereas the interjacent IL2-dependent proliferation of "step 1"-induced CTL precursors was unaffected by these antibodies. The anti-Lyt-2-mediated inhibition was selective and specific to the target cell determinants and limited to the events in CTL responses which require interactions with the lectins. These results parallel those obtained in antigen-induced responses and indicate that antigens and lectins induce CTL responses by interacting with the same type of membrane receptor complex containing Lyt-2 molecules and antigen-specific receptors. It follows that T cell mitogenic lectins do not appear to deliver triggering signals through "mitogen" receptors.

Animals↗
PubMed1983

Differential requirements for activation and growth of unprimed cytotoxic and helper T lymphocytes.

The requirements for activation and growth of T lymphocytes capable of mediating either cytolytic activity or help to B lymphocytes were studied in unprimed splenic T cell populations. The selectivity of expression of Lyt-2 antigens, the reactivity to soluble concanavalin A (Con A), to partially purified interleukin 2 (IL 2, T cell growth factor[s]) and to lectin-pulsed macrophages (M phi) were used in this analysis. Lectin-dependent cytotoxicity assays and a novel method that allows for the detection of all effector helper cells, regardless of their clonal specificities, were used for the functional identification of the responding T cells. The results show a marked contrast between cytolytic and helper T cells in their growth and activation requirements. Thus, while Lyt-2+ cytotoxic T lymphocyte precursors grow exponentially in IL 2 after a short pulse with soluble Con A in the absence of accessory cells, Lyt-2- helper cell precursors completely fail to proliferate under the same conditions and require the continuous presence of lectin-pulsed M phi for significant growth. Furthermore, addition of IL 2 to M phi-stimulated cultures of Lyt-2- cells has no effect. T cells which produce IL 2 have the same growth characteristics as helper cells. In both cases, effector helper functions could be expanded more than 10-fold on a per cell basis by a 5-day-culture period under those growth supporting conditions. The development of effector helper functions, however, was strongly inhibited by the presence of Lyt-2+ T cells.

Animals↗
PubMed1983

Selective functional role of murine Tm and Tg cells in concanavalin-A-induced T-cell activation.

Murine splenic cells were separated on Ig-anti-Ig columns to yield cell populations depleted of IgM-FcR (Fc receptor)-expressing (TM) and IgG-FcR-expressing (TG) cells and also cells expressing neither of these two FcR (TO). The proliferative response to the lectin concanavalin A (Con A) was shown to be present mainly in cell populations depleted of TM cells (T cells lacking IgM FcR)--that is, TM and TO. The low Con A response in the other cell populations, namely TG and TTOT, was due to a selection against T-cell growth factor (TCGF)-reactive cells, since TCGF production within these subsets was not impaired and the low proliferative response was not reconstituted by preformed TCGF. TG-cells were able to inhibit the Con-A-induced proliferation of TO and TM cells dose-dependently. These data strongly suggest the presence of a step-one regulatory, suppressive mechanism comprised within the TM population.

Animals↗
PubMed1983

Con A-induced TCGF-reactivity is selectively acquired by Lyt-2-positive T cell precursors.

We investigated whether concanavalin A-stimulated, TCGF-reactive, and TCGF-producing T cells could be separated with regard to their Lyt phenotypes. Normal spleen cells, pretreated with monoclonal anti-Lyt-1 or anti-Lyt-2 antibodies and complement were assayed for their capacity to respond to TCGF, as well as for their ability to produce TCGF after Con A stimulation. The results demonstrate that reactivity to TCGF is predominantly induced in Lyt-2+ lymphocytes, because it is reduced by more than 95% in Lyt-1+23- T cell populations as compared with cultures containing Lyt-1-23+ cells. Limiting dilution analysis revealed that up to 20% of the cells in Lyt-2-containing populations were induced by Con A to TCGF-reactivity, whereas 20-fold fewer clones were induced in the Lyt-2-depleted cell populations. On the other hand, the study of TCGF production in Lyt-1-23+ populations revealed that the former population was considerably enriched in TCGF-producing T cells, whereas the latter was substantially depleted. We conclude that TCGF-producing and TCGF-reactive T cells are largely distinct lymphocyte populations that can be separated on the basis of their Lyt phenotypes.

Animals↗
PubMed1982

Selective inhibition of antigen-induced "step one" in cytotoxic T lymphocytes by anti-Lyt-2 antibodies.

Stimulation of mixed lymphocyte cultures with ultraviolet (UV)-irradiated stimulator cells leads to selective activation of Lyt-2+ cytotoxic T lymphocyte precursors (CTL-P) to acquire interleukin 2 (IL2) reactivity: (a) no proliferative response, nor IL2 production was observed in these cultures; (b) upon addition of preformed IL2-conditioned media (IL2-CM), a vigorous proliferative response was observed; (c) the IL2-dependent proliferation was reduced by approximately 90% after depletion of Lyt-2+ responder cells; and (d) specific CTL were generated upon the initial triggering by UV-irradiated stimulators and IL2 expansion. This system therefore provides suitable conditions for studying the role of Lyt-2 antigens in initial, antigen-specific induction of CTL-P, as well as at their effector phase. It is shown herein that monoclonal anti-Lyt-2 antibodies inhibit antigen-specific acquisition of IL2 reactivity by CTL-P, which results in 85% reduction of the proliferative response mediated by IL2-CM. CTL-P which have been induced by antigen to IL2 reactivity, prior to addition of anti-Lyt-2 antibodies, however, are not affected in their IL2-dependent proliferation. Furthermore, both the specific and lectin-dependent cytolytic activity of effector CTL generated by UV-irradiated stimulators and IL2-CM is blocked by addition of anti-Lyt-2 antibodies in the cytotoxicity assay. The implications of these findings for the role of Lyt-2 antigen in antigen recognition by T cells are discussed.

Animals↗
PubMed1982

Selective effects of interferon on distinct sites of the T lymphocyte triggering process.

Lectin- and antigen-induced proliferation of murine T cells consists of two major events, namely, a rapid induction of susceptibility to growth factors and a later-occurring, accessory cell-dependent production of T cell growth factors (TCGF). The mechanism by which interferon (IFN) inhibits T cell responses was studied accordingly. A decrease of Con A-induced proliferation was observed in the presence of increasing amounts of IFN. The reduced proliferative response in such cultures was found to be due to an accumulation of cells in the G0/G1 phase of the cell cycle. Furthermore, the results show that IFN did not inhibit the early events in T cell triggering, because the acquisition of responsiveness of resting T cells to TCGF was unaltered in the presence of IFN, nor did it interfere with production of TCGF. In contrast, IFN was found to interfere with the TCGF-dependent T cell blast growth. Cytofluorometric analysis of the proliferative phase revealed that IFN exerts its effect on T cells, which have entered the proliferative cycle, by a postmitotic accumulation in G0/G1, thus reducing the proliferating population. The results demonstrate that IFN primarily affects the later phase of proliferative activity after T cell triggering, leaving the helper cell functions untouched.

Animals↗
PubMed1982

Studies on induction and effector functions of concanavalin A-induced suppressor cells that limit TCGF production.

The cellular mechanisms regulating TCGF production in Con A-stimulated cultures have been investigated. Normal spleen cells, activated by Con A for 24 hr, develop suppressive cells that inhibit de novo production of TCGF by fresh spleen cells. Effector cells mediating suppression are nonadherent, radioresistant, Lyt-2-positive T cells. The induction of suppressor cells is radiosensitive and it requires 18 hr. The kinetics of suppressor cell induction parallels very closely the termination of TCGF production in situ, suggesting the major importance of this mechanism in the control of TCGF production. Reculture of 24-hr Con A-activated cells in the absence of Con A for 24 to 72 hr results in a gradual loss of suppressive activity that can be recalled by readdition of Con A with the same kinetics found in fresh spleen cells. In addition, de novo production of TCGF is readily induced in such cultures upon restimulation with Con A, demonstrating that abrogation of TCGF-production in primary cultures is due to suppression and not to lectin-dependent killing of the TCGF-producing T cells. Measurements of suppressive activity and lectin-dependent cytotoxicity, in various populations of Con A-activated spleen cells, further distinguish these activities. Finally, the reduced suppressive activity of Con A-activated cells after expansion in TCGF excludes that suppressor cells act by absorption or removal of TCGF produced at normal rates. Direct, reversible suppression of TCGF-producing cells by T lymphocytes appears, therefore, to constitute a major mechanism by which cytotoxic T cell responses are regulated.

Animals↗
PubMed1982

Functional heterogeneity of helper T cells: two distinct helper T cells are required for the production of T cell growth factor.

A rat monoclonal antibody, obtained after immunization with cells from a cytolytic, TCGF-dependent T cell clone, was found to react with 10 to 20% of murine splenic and lymph node cells and with 65 to 70% of thymocytes. Addition of this antibody to normal spleen cell cultures, or cytotoxic elimination of the cells recognized by the antibody before culture, resulted in the abolishment or profound inhibition of the Con A-induced proliferative responses. The antibody did not react with or inhibit the proliferating, TCGF-reactive T cells, but it inhibited lectin-dependent TCGF production. An analysis of this inhibition, using purified cell populations and the macrophage-derived factor LAF, demonstrated that the cell removed by antibody cytotoxicity was neither the macrophage nor the TCGF-producing T cell, indicating that this antibody eliminates a second helper T cell required for lectin-dependent production of LAF by the accessory cells. These results extend previous observations on the T cell dependence of Con A-induced LAF production and identify a fourth cell type involved in the collaborative processes leading to TCGF-dependent T cell proliferation.

Animals↗
PubMed1981

Mechanism of T cell activation. II. Antigen- and lectin-dependent acquisition of responsiveness to TCGF is a nonmitogenic, active response of resting T cells.

Small resting T cells, which do not respond to T cell growth factor (TCGF), acquire responsiveness upon a short (4-hr) pulse of specific ligands by presenting growth receptors for TCGF. The results demonstrate that the same mechanisms operate in the specific induction of primary MLR in that a 5-hr MLR is sufficient to render the responder cells reactive to TCGF. Furthermore, the results demonstrate that an active "response" by the resting T cells is required for expression of functional growth receptors, as demonstrated by the fact that: 1) a 4-hr pulse of concanavalin A (Con A) at 4 degrees C did not result in gain of reactivity to TCGF, whereas a 4-hr pulse at 37 degrees C did; 2) this metabolic requirement for acquisition of responsiveness to TCGF was not due to a secondary requirement for cap-formation of Con A-binding membrane structures, as normal responses were observed in the presence of cytochalasin B (cyt B); 3) the process of Con A-induced acquisition of susceptibility to TCGF was puromycin sensitive.

Animals↗
PubMed1981

Regulation of T cell growth factor production: arrest of TCGF production after 18 hours in normal lectin-stimulated mouse spleen cell cultures.

The detailed kinetics of TCGF accumulation in Con A-stimulated spleen cell cultures shows a maximum at 24 hr, with a subsequent decrease in activity. This decrease is not due to the appearance of inhibitory substances "masking" TCGF activity. Pulse experiments show that the rate of TCGF production falls sharply after 18 hr and is completely arrested after 24 hr of Con A stimulation. The arrest in TCGF production is the result neither of culture depletion in medium components nor of limiting accessory cell function or inactivation of the lectin, and it thus seem to be the result of inactivation of TCGF-producing T cells. This regulation is not the result of a TCGF-mediated feedback mechanism but rather of lectin-induced suppressive cells that appear in culture after 24 hr and turn off de novo production of TCGF in fresh cultures.

Animals↗
PubMed1981

Quantitative studies on concanavalin A-induced, TCGF-reactive T cells. I. Correlation between proliferation and lectin-dependent cytolytic activity.

A limiting dilution assay was used to determine the frequencies of T cells that could be induced to proliferate and kill by Con A and TCGF. The frequency of proliferating cells was 1 in 5 nylon wool-purified spleen cells and 1 in 7 normal lymph node cells. The frequencies in the same cell populations of lectin-dependent killer cell precursors were 1 in 5 and 1 in 9, respectively. Even at limiting numbers of T cells seeded per culture, very few cultures proliferated without showing cytotoxic activity. Thus, under these conditions Con A and TCGF, preferentially if not exclusively, activate T cells that will kill in the presence of PHA. This experimental system can be used for estimating the repertoires of specific CTL-precursors activated by Con A and expanded in TCGF.

Animals↗