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PubMed1986

An in vitro model for clonal anergy in continuously growing antigen-specific B-cell lines.

Two continuously growing nonmalignant B-cell lines specific for the hapten DNP have been used to study tolerance in developing B cells. These cell lines have previously been shown to consist of small cells without sIgM but with cytoplasmic mu chains, and mature sIgM- and sIgD-bearing cells. When the sIgM-negative cells are placed in culture, mature DNP-specific B cells begin to appear. The studies reported here have shown that when these cell lines were propagated in the presence of either 200 micrograms/ml or 1 mg/ml of the tolerogen DNP-MGG there was no inhibition of cell line growth as measured by thymidine incorporation, and no inhibition of receptor expression by maturing B cells. The cell line lymphocytes propagated in the presence of 200 micrograms/ml DNP-MGG for 7, 30, 45, or 60 days became tolerant and the tolerance persisted for at least 6 days after removal of DNP-MGG. However, tolerance was lost between 6 and 10 days after removal of DNP-MGG. Propagation of the cell lines for 30 days in either DNP-KLH or DNP-Ficoll produced the same results. Limiting dilution cultures of cell line lymphocytes made tolerant by growing them for 30 days in the presence of DNP-MGG demonstrated that there was a marked decrease in precursor frequency compared to controls. However, cell line lymphocytes made tolerant by a 48-hr incubation with DNP-MGG did not have a significant decrease in precursor frequency. These data suggest that tolerance induced by growing these cell lines in the presence of DNP-MGG is a valid in vitro model of tolerance in developing antigen-specific B cells. Tolerance induced in this model is consistent with the clonal anergy hypothesis, but requires the continued presence of DNP-MGG to maintain unresponsiveness. This suggests that clonal anergy can occur in B cells but may not be the sole mechanism of self tolerance for those antigens which are sequestered from the immune system.

Animals↗
PubMed1983

Clonal anergy: inhibition of antigen-driven proliferation among single B lymphocytes from tolerant animals, and partial breakage of anergy by mitogens.

Mice were injected with fluoresceinated human gamma globulin (FLU-HGG) either at 2-3 days of age or as pregnant females. At 2 weeks of age, the spleen cells of the injected suckling mice or offspring were fractionated on FLU-gelatin dishes to yield FLU-binding B cells. These B cells were then cloned in microcultures using one of two recently described systems in which single B cells grow in the absence of feeder or filler cells, namely following stimulation with FLU-polymerized flagellin (FLU-POL) and conditioned media containing B cell growth and differentiation factor(s); or mitogenic activation by a mixture of E. coli lipopolysaccharide (LPS) and dextran sulfate (DxS). As such cultures permit visualization of clonal proliferation as well as ultimate harvesting of cultures for assay of hemolytic plaque-forming cells, it was possible to ask whether the lesion in the tolerant state affected the B cell's capacity to divide, to differentiate to antibody secretion, or both. The results indicated that, when stimulated with antigen, the anergic cells could neither divide nor differentiate. However, when the strong mitogen mixture was used, clonal anergy was partially broken. The cells proliferated, and a small proportion of them differentiated into anti-FLU antibody-forming cells. A marked variation in antigen-binding avidity of the FLU-binding cells made it difficult to quantitate the degree of uncoupling of proliferation and differentiation among tolerant, LPS plus DxS-stimulated cells. Nevertheless, a partial reversibility of clonal anergy must affect views on mechanisms of self-tolerance.

Animals↗
PubMed1996

Control of T lymphocyte signal transduction through clonal anergy.

Stimulation of interleukin-2 producing T lymphocytes via the T cell receptor (TCR) complex in the absence of other costimulatory factor results paradoxically not in activation but in an unresponsive state termed clonal anergy. T cell anergy appears to be a mechanism by which potentially autoreactive T lymphocytes are inactivated in the periphery, thus maintaining tolerance to self antigens. The breakdown of such tolerance may result in autoimmune diseases. In contrast, induction of peripheral tolerance is the ultimate goal in organ transplantation and is a potential mechanism by which a growing tumor evades immune destruction. The anergic state is characterized by an inability to secrete interleukin-2 and proliferate following restimulation via the TCR even in the presence of constimulatory factors. Recent studies have demonstrated a specific block in Ras activation in anergic T lymphocytes. This defect is correlated with a failure to activate the downstream effectors Erk and Jnk and a lack of activation of the AP-1 transcription factor complex, offering a plausible mechanism for the inability to initiate interleukin-2 gene transcription in the anergic state.

Cell Differentiation↗
PubMed1994

CD2 is involved in maintenance and reversal of human alloantigen-specific clonal anergy.

Induction and maintenance of a state of T cell unresponsiveness to specific alloantigen would have significant implications for human organ transplantation. Using human histocompatibility leukocyte antigen DR7-specific helper T cell clones, we demonstrate that blockade of the B7 family of costimulatory molecules is sufficient to induce alloantigen-specific T cell clonal anergy. Anergized cells do not respond to alloantigen and a variety of costimulatory molecules, including B7-1, B7-2, intercellular adhesion molecule-1 (ICAM-1), and lymphocyte function-associated molecule (LFA)-3. However, after culture in exogenous interleukin (IL)-2 for at least 7 d, anergized cells can respond to alloantigen in the presence of LFA-3. LFA-3 costimulation subsequently restores responsiveness to alloantigen in the presence of previously insufficient costimulatory signals. Expression of CD2R epitope is downregulated on anergic cells and is restored after 7 d of IL-2 culture. The loss of the CD2R is temporally associated with the inability of anergized cells to respond to LFA-3. These results suggest that in addition to blockade of B7 family members, inhibition of CD2 and, potentially, other costimulatory pathways that might reverse anergy will be necessary to maintain prolonged alloantigen-specific tolerance.

Abatacept↗
PubMed1994

Induction of clonal anergy by oral administration of staphylococcal enterotoxin B.

The staphylococcal enterotoxin is a major cause of food poisoning. The bacterial substance stimulates T cells expressing specific V beta T cell receptors (TcR) and is termed "the superantigen". We have previously demonstrated that intravenous injection of staphylococcal enterotoxin B (SEB) induces functional unresponsiveness (anergy) of reactive T cells as well as a partial deletion by activation-induced programmed cell death. In the present study, we examined the effect of oral administration of SEB in mice. Our results indicate that spleen T cells from SEB-primed mice are hyporesponsive to SEB stimulation in vitro, but the response to SEA was normal. V beta 8+ T cells purified from SEB-primed mice did not respond to stimulation of TcR. This SEB-specific unresponsiveness could not be reversed by exogenous interleukin-2, but was partially reversed by phorbol 12-myristate 13-acetate. Activation of mitogen-activated protein kinase during TcR-mediated stimulation was significantly inhibited in anergic T cells. Although the mechanisms of oral tolerance are not well understood, these results show that oral administration of SEB induce clonal anergy in peripheral T cells.

Administration, Oral↗
PubMed2001

Antagonistic roles for CTLA-4 and the mammalian target of rapamycin in the regulation of clonal anergy: enhanced cell cycle progression promotes recall antigen responsiveness.

CD4(+) T cells that undergo multiple rounds of cell division during primary Ag challenge in vivo produce IL-2 on secondary Ag rechallenge, whereas cells that fail to progress through the cell cycle are anergic to restimulation. Anti-CTLA-4 mAb treatment during primary Ag exposure increases cell cycle progression and enhances recall Ag responsiveness; however, simultaneous treatment with rapamycin, an inhibitor of the mammalian target of rapamycin and potent antiproliferative agent, prevents both effects. The data suggest that cell cycle progression plays a primary role in the regulation of recall Ag responsiveness in CD4(+) T cells in vivo. CTLA-4 molecules promote clonal anergy development only indirectly by limiting cell cycle progression during the primary response.

Abatacept↗
PubMed2001

Fas/Fas ligand pathway, apoptosis, and clonal anergy involved in systemic acetylcholine receptor T cell epitope tolerance.

The cellular mechanisms of high dose systemic acetylcholine receptor (AChR) T cell epitope, alpha 146--162 peptide-induced tolerance in experimental myasthenia gravis were examined. CD4 cells are the prime target for alpha 146--162 peptide-induced tolerance. The expression of CD69, Fas, and B7.2 molecules on AChR-immune lymphocytes was enhanced within 4--12 h after tolerance induction. A high dose of alpha 146--162 peptide in IFA failed to suppress T cell proliferation and/or clinical myasthenia gravis in lpr and gld mice deficient in Fas and Fas ligand, respectively. A high dose of alpha 146--162 peptide in IFA in AChR-immunized mice induced apoptosis of BV6 cells. Further, reconstitution of IL-2 in vitro-recovered alpha 146--162 peptide tolerized T cell proliferation, IFN-gamma, and IL-10 production. The findings implicate the possible role of Fas-/Fas ligand-mediated apoptosis and the resulting clonal anergy as the mechanisms of high dose AChR alpha 146--162 peptide-induced tolerance on CD4 cells.

Adjuvants, Immunologic↗
PubMed1997

Clonal anergy is a potent mechanism of oral tolerance in the suppression of acute antigen-induced arthritis in rats by oral administration of the inducing antigen.

The effects of oral administration of ovalbumin (OVA) on acute OVA-induced arthritis (OIA) in rats, which is mediated by Arthus reaction to the antigen in the joint space, were investigated. The oral administration of OVA before immunization with OVA significantly suppressed the development of acute OIA in a dose-dependent manner, in accordance with decreases in both the in vivo anti-OVA IgG antibody production and in vitro lymphocyte proliferative responses to OVA. These results were shown in both the single high-dose (200 mg x 1) or the multiple low-dose (200 microg x 5) feeding protocols. In vitro study showed that rat IL-2 could reverse the reduced OVA-specific lymphocyte proliferative responses. The spleen cells obtained from OVA-feeding, unprimed rats neither adoptively transferred the suppression to naive recipient rats nor suppressed the in vitro lymphocyte proliferation. These results demonstrate that the acute OIA can be suppressed by the induction of oral tolerance (OT) to OVA, and strongly suggest that the OT was due to clonal anergy of antigen-reactive T lymphocytes, not the active suppression by OVA-specific regulatory cells.

Acute Disease↗
PubMed2006

Essential role of membrane cholesterol in accelerated BCR internalization and uncoupling from NF-kappa B in B cell clonal anergy.

Divergent hypotheses exist to explain how signaling by the B cell receptor (BCR) is initiated after antigen binding and how it is qualitatively altered in anergic B cells to selectively uncouple from nuclear factor kappaB and c-Jun N-terminal kinase pathways while continuing to activate extracellular signal-regulated kinase and calcium-nuclear factor of activated T cell pathways. Here we find that BCRs on anergic cells are endocytosed at a very enhanced rate upon binding antigen, resulting in a large steady-state pool of intracellularly sequestered receptors that appear to be continuously cycling between surface and intracellular compartments. This endocytic mechanism is exquisitely sensitive to the lowering of plasma membrane cholesterol by methyl-beta-cyclodextrin, and, when blocked in this way, the sequestered BCRs return to the cell surface and RelA nuclear accumulation is stimulated. In contrast, when plasma membrane cholesterol is lowered and GM1 sphingolipid markers of membrane rafts are depleted in naive B cells, this does not diminish BCR signaling to calcium or RelA. These results provide a possible explanation for the signaling changes in clonal anergy and indicate that a chief function of membrane cholesterol in B cells is not to initiate BCR signaling, but instead to terminate a subset of signals by rapid receptor internalization.

Animals↗
PubMed1990

Clonal deletion and clonal anergy in the thymus induced by cellular elements with different radiation sensitivities.

The present study demonstrates that immune tolerance can be achieved in the thymus both by clonal deletion and by clonal inactivation, but that the two tolerant states are induced by cellular elements with different radiation sensitivities. TCR engagement of self antigens on bone marrow-derived, radiation-sensitive (presumably dendritic) cells induces clonal deletion of developing thymocytes, whereas TCR engagement of self antigens on radiation-resistant cellular elements, such as thymic epithelium, induces clonal anergy. The nondeleted, anergic thymocytes can express IL-2-Rs but are unable to proliferate in response to either specific antigen or anti-TCR antibodies, and do develop into phenotypically mature cells that emigrate out of the thymus and into the periphery.

Animals↗
PubMed1992

The role of cell division in the induction of clonal anergy.

The interaction of antigen with lymphocyte antigen receptors can result in either clonal expansion or unresponsiveness (anergy). In 1970, Bretscher and Cohn proposed a two-signal model of lymphocyte activation to explain this paradox: antigen receptor occupancy alone could induce unresponsiveness whereas antigen receptor occupancy plus a costimulatory signal could induce immunity. Here, Marc Jenkins reviews in vitro and in vivo manifestations of clonal anergy and evaluates the ability of the two-signal model to explain these phenomena.

Animals↗
PubMed1989

Clonal anergy induced in mature V beta 6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells.

Tolerance to self-antigens has been shown to develop during ontogeny as a result of the clonal deletion of self-reactive T cells. Tolerance, or better 'nonresponsiveness', to specific antigens can also be induced in adult animals but the mechanism(s) involved are not well understood. Most murine T-helper cells that express the V beta 6 T-cell receptor gene segment are specific for Mls-1a antigens. We have therefore been able to use an anti-V beta 6 monoclonal antibody to follow the fate of Mls-1a specific T cells in adult Mls-1b mice made specifically unresponsive to Mls-1a. We show that the induced unresponsiveness is not due to clonal deletion, but rather to clonal anergy. The anergic V beta 6 T-helper cells express IL-2 receptors and undergo limited blastogenesis in vitro upon stimulation, but do not produce IL-2, in marked contrast to V beta 6 cells from naive mice. Our data appear to represent an in vivo correlate for the induction of anergy that has been observed in T-cell lines in vitro.

Animals↗
PubMed1980

Clonal anergy: persistence in tolerant mice of antigen-binding B lymphocytes incapable of responding to antigen or mitogen.

The purpose of these experiments was to determine the degree of reduction in the number of antigen-binding B lymphocytes in the spleens of mice that had been rendered tolerant in the perinatal period. Newborn or pregnant mice were injected with fluorescein (Flu) coupled onto human gamma globulin, and the spleen cells of the neonatally injected mice, or of the offspring of the pregnant mice, were analyzed 1-6 weeks later. Tolerogen doses were chosen so as to achieve either a two-thirds reduction (low dose) in the number of anti-Flu B cells capable of yielding anti-hapten plaque-forming cell clones after in vitro stimulation, or as representing a supra-optimal tolerogenic stimulus (high dose). Antigen-binding B cells were studied by a two-cycle procedure, namely an initial cycle of binding to Flu-gelatin thin layers, followed by analysis of the binding cells in the fluorescence-activated cell sorter (FACS) after suitable staining with Flu-protein conjugates. With the high dose of tolerogen, a modest diminution in Flu-binding cell numbers down to 56-71% of control values could be induced. When these residual Flu-specific B cells were analyzed in the FACS to quantitate their spectrum of Flu-binding avidities, profiles identical to those of controls were obtained. The reduction proved transient in nature, binding cell numbers having returned to 80% of normal by 2 weeks and to normal by 6 weeks. Nevertheless, the Flu-specific B cells were incapable of responding to antigen or mitogen by antibody formation. With the low dose of tolerogen, despite the desired degree of functional silencing of Flu-specific B cells, the numbers and avidity spectra of antigen-binding cells were entirely normal in both the neonatally injected and in utero-injected groups. The results indicate that tolerance induced amongst immature B lymphocytes is not due to a physical elimination of the relevant B cell clones or to a modulation or blockade of their surface Ig receptors. Rather, it is due to the recognition and storage of negative signals amongst cells that continue to display a normal complement of receptors. We therefore propose that the term "clonal anergy" is a more accurate description than either "clonal deletion" or "clonal abortion."

Animals↗
PubMed1992

Reversal of in vitro T cell clonal anergy by IL-2 stimulation.

Stimulation of a normal type I mouse T helper cell clone (TH1) with concanavalin A in the absence of antigen presenting cells (APC) in vitro results in the induction of a hyporesponsive state known as T cell clonal anergy. This state is characterized by a decrease in proliferation following stimulation with antigen and APC resulting from a decrease in the production of IL-2. Production of the lymphokines IL-3/granulocyte macrophage colony stimulating factor and IFN-gamma is also reduced, although to a lesser degree. Stimulation of such anergic cells with IL-2 results in proliferation and a complete reversal of the state. We demonstrate that this reversal is not due to the outgrowth of a subpopulation of cells that had escaped anergy induction, but rather occurs in all the cells. Anergy also dissipated spontaneously, although much more slowly, in the absence of T cell antigen receptor occupancy. Finally, we show that a similar state can be produced by normal activation with antigen and APC if IL-2 and other factors are removed at 16-20 h. These results indicate that the anergic state is not a permanent change in the TH1 cell. Anergy induction appears to be a consequence of the inability of the cell to divide extensively following stimulation through the antigen-specific receptor. We propose a model to explain these results in terms of a relatively stable negative regulatory factor.

Animals↗
PubMed1990

Clonal deletion versus clonal anergy: the role of the thymus in inducing self tolerance.

During development in the thymus, T cells are rendered tolerant to self antigens. It is now apparent that thymocytes bearing self-reactive T cell receptors can be tolerized by processes that result in physical elimination (clonal deletion) or functional inactivation (clonal anergy). As these mechanisms have important clinical implications for transplantation and autoimmunity, current investigations are focused on understanding the cellular and molecular interactions that generate these forms of tolerance.

Animals↗
PubMed1990

Distinct fates of self-specific T cells developing in irradiation bone marrow chimeras: clonal deletion, clonal anergy, or in vitro responsiveness to self-Mls-1a controlled by hemopoietic cells in the thymus.

Elimination of potentially self-reactive T lymphocytes during their maturation in the thymus has been shown to be a major mechanism in accomplishing self-tolerance. Previous reports demonstrated that clonal deletion of self-Mls-1a-specific V beta 6+ T lymphocyte is controlled by a radiosensitive I-E+ thymic component. Irradiation chimeras reconstituted with I-E- bone marrow showed substantial numbers of mature V beta 6+ T cells despite host Mls-1a expression. Analysis of the functional properties of such chimeric T cells revealed a surprising variability in their in vitro reactivity to host Mls-1a, depending on the H-2 haplotype of stem cells used for reconstitution. In chimeras reconstituted with B10.S (H-2s) stem cells, mature V beta 6+ lymphocytes were present but functionally anergic to host-type Mls-1a in vitro. In contrast, in chimeras reconstituted with B10.G (H-2q) bone marrow, nondeleted V beta 6+ cells were highly responsive to Mls-1a in vitro. These findings suggest that clonal anergy of V beta 6+ cells to self-Mls-1a may be controlled by the affinity/avidity of T cell receptor interactions with bone marrow-derived cells in the thymus depending on the major histocompatibility complex class II molecules involved. Furthermore, chimeras bearing host (Mls-1a)-reactive V beta 6+ cells did not differ clinically from those with anergic or deleted V beta 6+ cells and survived more than one year without signs of autoimmune disease. Interestingly, their spleen cells had no Mls-1a stimulatory capacity in vitro. Therefore, regulation at the level of antigen presentation may be an alternative mechanism for maintenance of tolerance to certain self-antigens such as Mls-1a.

Animals↗
PubMed1993

Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation.

The maximal T-cell response to its antigen requires presentation of the antigen by a major histocompatibility complex class II molecule as well as the delivery of one or more costimulatory signals provided by the antigen-presenting cell (APC). Although a number of candidate molecules have been identified that are capable of delivering a costimulatory signal, increasing evidence suggests that one such critical pathway involves the interaction of the T-cell surface antigen CD28 with its ligand B7, expressed on APCs. In view of the number of potential costimulatory molecules that might be expressed on the cell surface of APCs, artificial APCs were constructed by stable transfection of NIH 3T3 cells with HLA-DR7, B7, or both. Here, we show that in a human antigen-specific model system, when tetanus toxoid peptide antigen is presented by cells cotransfected with HLA-DR7 and B7, optimal T-cell proliferation and interleukin 2 production result. In contrast, antigen presentation, in the absence of B7 costimulation, results in T-cell clonal anergy. These results demonstrate that it is possible to induce antigen-specific clonal tolerance in human T cells that have been previously sensitized to antigen. The artificial antigen-presenting system provides a useful model for the investigation of the biochemical events involved in the generation of tolerance and for the study of signals necessary to overcome tolerance.

Amino Acid Sequence↗
PubMed1993

Clonal anergy to staphylococcal enterotoxin B in vivo: selective effects on T cell subsets and lymphokines.

Injection of bacterial superantigens such as staphylococcal enterotoxin B (SEB) in adult mice results in initial proliferation of SEB-responsive V beta 8+ T cells followed by induction of a state of non-responsiveness frequently referred to as clonal anergy. We show here that SEB-induced anergy involves selective changes in lymphokine production and that it affects CD4+ V beta 8+ and CD8+ V beta 8+ T cells in different fashions. Whereas both CD4+ V beta 8+ and CD8+ V beta 8+ cells from anergic mice exhibit strongly reduced proliferative capacity and interleukin(IL)-2 production upon restimulation with SEB either in vivo or in vitro the CD8+ subset from SEB-injected mice produces other lymphokines (such as interferon(IFN)-gamma) at normal or slightly increased levels in response to SEB. Changes in the levels of production of IL-2 and IFN-gamma protein correlated well with mRNA accumulation both in vivo and in vitro. Collectively these data suggest that superantigen-induced anergy involves selective changes in signal transduction and/or gene regulation in T lymphocytes.

Animals↗