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PubMed2000

Highly autoproliferative T cells specific for 60-kDa heat shock protein produce IL-4/IL-10 and IFN-gamma and are protective in adjuvant arthritis.

Previously we have shown that T cell responses to the mycobacterial 60-kDa heat shock protein (hsp60) peptide M256-270 mediated protection against adjuvant arthritis in Lewis rats. We have demonstrated now that M256-270-primed T cells become highly reactive to naive syngeneic APC upon repetitive restimulation in vitro with peptide M256-265, comprising the conserved core of peptide M256-270. These autoproliferative responses in the absence of added Ag were MHC class II restricted and resulted in the production of IL-4/IL-10 and IFN-gamma. Enhanced autoproliferation and expression of the cell surface molecule B7.2 by these T cells were observed in response to syngeneic heat-shocked APC, which indicated that the autoproliferation and expression of B7.2 resulted from the recognition of endogenously expressed and processed hsp. Despite their strong autoreactivity, upon transfer such T cells were found to induce a significant disease reduction in adjuvant arthritis. In contrast, T cells both primed and restimulated with peptide M256-270 became unresponsive toward syngeneic APC as well as toward the conserved core peptide M256-265, and they were devoid of protective capacity. This study demonstrates that the loss of self-tolerance toward hsp60 does not necessarily lead to autoimmune disease, but that hsp60-specific self-reactive and autoproliferative T cells may mediate T cell regulation in arthritis.

Amino Acid Sequence↗
PubMed1999

Development and tolerance of natural killer cells.

A natural killer (NK)/T-cell-restricted progenitor cell in the fetal blood, with a phenotype of NK1.1(+) CD117 (c-kit)+, can give rise to NK cells. IL-15 is probably required for NK cell differentiation and, in addition, stimulates expression of at least one of the MHC-specific inhibitory receptor families expressed by NK cells. Evidence supports the role of multiple mechanisms in rendering NK cells self tolerant - including selection for expression of self-specific inhibitory receptors, anergy and modulation of the cell surface levels of MHC-specific inhibitory receptors.

Animals↗
PubMed1983

Cells in murine fetal liver and in lymphoid colonies grown from fetal liver can suppress generation of cytotoxic T lymphocytes directed against their self antigens.

Fetal liver (FL) cells or, in much smaller numbers, cells in lymphoid colonies grown from FL of mouse strain A can suppress the development of cytotoxic activity in a B anti-A mixed lymphocyte reaction (MLR) but not a B anti-C MLR. A, B, and C represent three H-2 different mouse strains. Suppressor cells with similar properties have been described in thymus, bone marrow, lymphoid colonies grown from bone marrow, and athymic nude spleen. They have been referred to collectively as "veto cells". From the point of view of the suppressor cells, a response against self is being suppressed. The FL colony suppressor cells differ from those described in that they can sometimes also suppress an A anti-B response. The FL colony suppressor cells are Thy-1- and resistant to 1500 rad irradiation. These cells may play a role in maintenance of self tolerance. That they are found in FL as early as 13 days of gestation implies that potentially self-reactive cells may develop before experiencing the thymus environment.

Animals↗
PubMed1992

Specialization, tolerance, memory, competition, latency, and strife among T cells.

Over the last four decades much insight has been gained into the working of T cells. This survey offers an interpretation of regulatory T-cell function in terms of epitope linkage and the need to free B cells of responsibility for self-tolerance. These functions dictate specialized forms of antigen presentation, by separate populations of dendritic cells. Tolerance induction among T cells occurs at a threshold of antigen concentration which is close to that required for positive stimulation, as would be expected for the efficient working of the immune system. Certain self-proteins, especially those located on cell surfaces, also induce tolerance among B cells, thus reducing the danger of activating latent epitopes. Memory among T cells is attributed to two components, one of hyperreactivity of activated cells, and the other of clonal expansion. Examples of competition and buffering between T-cell activities are given. A brief discussion of autoimmune disease focusses on the importance of disease remission, protective HLA genes, and immunoinhibitory genes in animal models. The mechanism underlying all three may be a balance between competing subsets of T cells.

Autoimmunity↗
PubMed1996

Tolerance is overcome in beef insulin-transgenic mice by activation of low-affinity autoreactive T cells.

To gain insight into the factors controlling the maintenance or loss of T cell self tolerance we produced beef insulin (BI)-transgenic BALB/c mice. Transgenic mice express BI under control of the human insulin promoter and secrete physiological amounts of beef insulin. Although these mice are tolerant to BI, as evidenced by the lack of insulin-specific IgG antibody production following intraperitoneal immunization, tolerance is not complete. Footpad immunization results in a weak antigen-specific T cell proliferative response, indicating the presence of self-reactive BI-specific T cell in the periphery. These T cells are functional in vivo, providing support for IgG1, IgG2a, and IgG2b BI-specific antibody production, but require higher higher concentrations of antigen than nontransgenic T cells (both in vivo and following recall responses in vitro) to become activated. In vitro, BI-specific T cell proliferation in BI-transgenic mice can be largely restored by addition of interleukin-2, indicating that a significant component of T cell tolerance is mediated by anergy. To characterize the autoreactive T cells that become activated when tolerance is broken, BI-specific T cell hybridomas were generated from transgenic mice and compared to a panel of hybridomas previously derived from nontransgenic BALB/c mice. The majority of BI-transgenic hybridomas recognized the immunodominant A1-14 beef insulin peptide but with lower avidity than BALB/c hybridomas. Consistent with this, none of the dominant T cell receptor rearrangements found in the BALB/c BI-specific T cell receptor repertoire were found in the transgenic hybridomas. These results indicate that, despite evidence for clonal inactivation of many BI-specific T cells in BI-transgenic mice, loss of tolerance results from activation of low-affinity antigen-specific T cells that appear to have escaped this process.

Amino Acid Sequence↗
PubMed1997

Do holes in the T-cell repertoire have a center-surround regulatory structure? A rationale for the bifurcation of the Th1 and Th2 pathways of differentiation.

Regulatory strategies controlling the balance of Th1 versus Th2 T-helper cell responses have been a long-standing mystery with important consequences for immunological disease. A novel model is presented to explain the comparative differentiation of Th1 and Th2 T cells as part of a mechanism to ensure self-tolerance. This model is based on the assumption that thymic interactions of T cell antigen receptors with self major histocompatibility complex ligands may vary in efficacy. By this model, fully agonistic major histocompatibility complex ligands elicit apoptosis during thymic selection to generate 'holes' in the repertoire. Conversely, major histocompatibility complex ligands having some degree of partial efficacy (i.e. a mixed agonist/antagonist) may promote Th2 differentiation whereas fully antagonistic major histocompatibility complex ligands elicit Th0 differentiation. Differentiation of Th2 T cells may continue in the extrathymic tissues upon continued interactions with self major histocompatibility complex ligands having mixed agonist/ antagonist properties. By this mechanism, each 'hole' in the repertoire will develop an inhibitory surround comprised to Th2 T cell clones having partial reactivities to a particular self major histocompatibility complex ligand. During immune responses to self-mimicking foreign antigens, the more numerous Th2 T cells of the inhibitory surround would prevent clonal expansion and Th1 differentiation of any fully autoreactive T cell.

Animals↗
PubMed2000

Dominant tolerance and linked suppression induced by therapeutic antibodies do not depend on Fas-FasL interactions.

BACKGROUND: Nonlytic anti-CD4 monoclonal antibody therapy can be used to induce transplantation tolerance in rodent models. Such tolerance is often associated with dominant regulation, mediated by CD4+ cells, and characterized by infectious tolerance and linked suppression. Understanding the mechanisms by which CD4+ regulatory cells function may improve the manner in which current immunosuppressants are applied and may lead to the development of new tolerance-inducing therapeutics. Fas-mediated apoptosis has been characterized as an important mechanism of peripheral self-tolerance and we here examine whether it has any role in anti-CD4 monoclonal antibody-induced dominant tolerance. METHODS: Tolerance to transplanted skin and bone marrow, mismatched for multiple minor histocompatibility antigens, was induced in Fas mutant and control mice using anti-CD4 and anti-CD8 monoclonal antibodies. To test for linked suppression, animals were transplanted with a second graft-bearing tolerated and third party antigens. The ability of splenocytes from tolerant animals to suppress graft rejection was assessed by transfer into partially immunocompromised recipients. RESULTS: Monoclonal antibody therapy rendered Fas mutant mice tolerant of minor disparate skin and bone marrow. Splenocytes from these and control tolerant animals when transferred into partially immunocompromised Fas mutant or control recipients, induced antigen-specific suppression of graft rejection. Additionally, tolerant Fas mutant mice accepted grafts bearing tolerated and third party antigens. CONCLUSIONS: Signal transduction through the Fas receptor plays no essential role in the induction of tolerance using anti-CD4 and anti-CD8 monoclonal antibodies or its maintenance by active regulation.

Animals↗
PubMed2005

The B7 family revisited.

The discovery of new functions for the original B7 family members, together with the identification of additional B7 and CD28 family members, have revealed new ways in which the B7:CD28 family regulates T cell activation and tolerance. B7-1/B7-2:CD28 interactions not only promote initial T cell activation but also regulate self-tolerance by supporting CD4+CD25+ T regulatory cell homeostasis. CTLA-4 can exert its inhibitory effects in both B7-1/B7-2 dependent and independent fashions. B7-1 and B7-2 can signal bidirectionally by engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells. The five new B7 family members, ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1) are expressed on professional antigen-presenting cells as well as on cells within nonlymphoid organs, providing new means for regulating T cell activation and tolerance in peripheral tissues. The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and they have important roles in regulating previously activated T cells. PD-1 and BTLA also are expressed on B cells and may have broader immunoregulatory functions. The ICOS:ICOSL pathway appears to be particularly important for stimulating effector T cell responses and T cell-dependent B cell responses, but it also has an important role in regulating T cell tolerance. In addition, the PD-1:PD-L1/PD-L2 pathway plays a critical role in regulating T cell activation and tolerance. In this review, we revisit the roles of the B7:CD28 family members in regulating immune responses, and we discuss their therapeutic potential.

Animals↗
PubMed2001

A nondeletional mechanism for central T-cell tolerance.

To be positively selected, immature thymocytes must receive signaling through their T-cell receptor (TCR), and engagement of relatively low-affinity self-peptides permits further T-cell maturation. However, mature T cells no longer overtly respond to such low-affinity antigens, indicating that T cells acquire a higher threshold for activation during thymopoiesis. We wondered whether partial interference in positive selection could produce T cells that respond to the selecting self-peptide. This possibility was tested by injecting procainamide-hydroxylamine (PAHA), a lupus-inducing drug, into the thymus of adult normal mice. Three weeks after the second injection, IgG antichromatin antibodies appeared in the circulation and remained for several months. The murine antichromatin antibodies reacted with the (H2A-H2B)-DNA subnucleosome complex, the predominant specificity in patients with procainamide-induced lupus. In thymus organ and reaggregate cultures, PAHA had no effect on negative selection of T cells with high affinity for a co-present antigen, but acted on CD4+ CD8+ immature T cells as they underwent positive selection. TCR transgenic T cells specific to cytochrome c peptide 88-104 acquired the capacity to respond to the low-affinity analogue at position 99 (lys-->ala) if PAHA was present during their development. PAHA also blocked the capacity of a T-cell line to become anergic after anti-CD3 treatment, suggesting that PAHA prevents the production of negative regulators that accumulate in response to partial signaling through the TCR. These results are consistent with the view that T cells acquire self-tolerance during positive selection, and disruption of this process can result in autoreactive T cells and systemic autoimmunity.

Animals↗
PubMed1987

Specific suppression elicited by EL4 lymphoma cells in syngeneic mice. Specificity includes self-antigens on EL4.

In vivo, subclones derived from EL4 lymphoma cells generate suppressor T lymphocytes specific for anti-EL4 immune responses. Spleen cells of EL4-sensitized C57BL/6 mice down-regulate the in vitro induction of EL4-specific cytolytic T lymphocytes (CTL). In addition, EL4-sensitized spleen cells interfere with the antigen response of two T lymphocyte clones. These recognize, in an H-2b context, a self-antigen on spleen cells that is also expressed by transformed cells, including EL4. The simultaneous anti-self and anti-EL4 specificity of the helper and suppressor activities suggests, therefore, that they are the product of an in vivo autoimmune reaction to EL4. The anti-self suppression might aim to re-establish self-tolerance, at the same time down-regulating responses against immunogenic epitopes that are co-expressed with the self-antigen on the EL4 cells. This agrees well with our observation that suppressor T cells, apparently elicited by suppressogenic epitopes on non-immunogenic EL4 subclones, down-regulate the CTL response elicited by immunogenic EL4 subclones. The additional self-specificity of this suppression indicates that the suppressogenic epitopes at least in part represent EL4 self-antigens.

Animals↗
PubMed2000

Targeting p53, hdm2, and CD19: vaccination and immunologic strategies.

Peptides presented by class I major histocompatibility complex (MHC) molecules and derived from normal self-proteins that are expressed at elevated levels by cells from a variety of human (Hu) malignancies provide, in theory, potential target antigens for a broad-spectrum, cytotoxic T lymphocyte (CTL)-based immunotherapy of cancer and hematologic malignancies. However, as such tumor- and leukemia-associated self-proteins are also expressed at low levels in some types of normal tissues, such as thymus, spleen and lymphohemopoietic cells, these self-MHC-self-peptide complexes may also represent thymic and/or peripheral tolerogens, thereby preventing immune responses. This is particularly true for class I MHC-peptide complexes expressed by bone marrow-derived cells in the thymus, as such expression would cause negative selection of immature thymic T cells with high avidity for self-MHC-self-peptide complexes. This intrathymic deletion of potentially self-reactive T cells could result in a peripheral T cell repertoire purged of CTL precursors with sufficient avidity to recognize natural tumor associated self-epitopes presented by class I MHC molecules on tumor cells. HLA-transgenic (Tg) mice provide the basis of an experimental strategy that exploits species differences between Hu and murine (Mu) protein sequences in order to circumvent self-tolerance and obtain HLA-restricted CTL specific for epitopes derived from tumor- and leukemia-associated Hu self proteins, such as p53, Her-2/neu, hdm2 and CD19.

Animals↗
PubMed2003

CD40 and dendritic cell function.

CD40 has emerged as a key signaling pathway for the function of B cells, monocytes, and dendritic cells (DC) in the immune system, and plays a major role in inflammatory pathways of nonhemopoietic cells. CD40 is expressed by monocytes and DC and is up-regulated when DC migrate from the periphery to draining lymph nodes (DLN) in response to microbial challenge. CD154 signaling by MHC-restricted, activated CD4+ T cells induces differentiation of DC, as defined by an increased surface expression of MHC, costimulatory, and adhesion molecules. Thus, CD40 functions in the adaptive immune response as a trigger for the expression of costimulatory molecules for efficient T-cell activation. CD40 ligation of DC also has the capacity to induce high levels of the cytokine IL-12, which polarizes CD4+ T cells toward a T helper 1 (Th1) type, enhances proliferation of CD8+ T cells, and activates NK cells. CD40 may also play an important role in the decision between tolerance and immunity and the generation of regulatory CD4+ T cells that are thought to maintain peripheral self-tolerance in vivo.

Animals↗
PubMed1975

Autoimmunity: present concepts.

Autoimmune disease may be effected by humoral mechanisms (direct antibody effect or pathogenic antigen-antibody complexes), cell-mediated mechanisms, and possibly complement in the absence of antibody. In view of recent work, self-tolerance can no longer be explained by the clonal selection theory; cells that are capable of recognizing self-antigens and effecting an autoimmune response seem to be present in the normal individual but actively regulated by a process involving antigen-antibody complexes or suppressor T cells. The determination that a clinical state is an autoimmune disease cannot, therefore, be made only on the basis of the presence of autoantibody as this may be part of the normal and active state of immunoregulation of autoimmunity. Indeed, the absence of autoantibody may be the immunodeficient state that allows a full-blown autoimmune disease to occur. In view of this knowledge, the basis for the diagnosis of autoimmune disease and the rationale for treatment based on the objective of inhibiting all immune responses to the autoantigen require re-examination.

Animals↗
PubMed1995

Identification and characterization of a major tolerogenic T-cell epitope of type II collagen that suppresses arthritis in B10.RIII mice.

Tolerization of B10.RIII mice (H-2r) with intravenously injected type II collagen (CII) renders the animals resistant to induction of collagen-induced arthritis (CIA). In order to clarify H-2r-restricted T-cell responses that modulate CIA, we have analysed the T-cell proliferative response of B10.RIII mice against cyanogen bromide (CB) peptides of CII, and detected the strongest response to alpha 1(II)-CB10 (CII 552-897). A panel of chemically synthesized overlapping peptide homologues was used to deduce the minimum structure of this determinant which was found to be CII 610-618. A 15-residue synthetic peptide flanking this region, CII 607-621, was found to effectively suppress arthritis when administered as a tolerogen. Collectively, these data identify the structural component within alpha 1(II)-CB10 which is capable of inducing tolerance in B10.RIII mice. A similar approach to the treatment of autoimmune arthritis, involving the institution of self-tolerance, has potential applicability to human rheumatoid arthritis.

Amino Acid Sequence↗
PubMed1995

Human immunoglobulin (IgG) induced deletion of IgM rheumatoid factor B cells in transgenic mice.

The singular ability of immunoglobulin genes to hypermutate their variable regions, while permitting the generation of high-affinity antibodies against foreign antigens, poses a problem in terms of maintenance of immunological self-tolerance. Immunoglobulin gene hypermutation driven by a foreign antigen has the potential to generate antibodies that cross-react with self-components. Consequently, there must exist a mechanism in the periphery for inactivation of mature autoreactive B cell clones. The classical experimental system used to address this problem is the induction of tolerance to soluble, deaggregated human IgG. We have analyzed the mechanism of induction of tolerance to human IgG using transgenic mice that express a human IgM rheumatoid factor (IgM RF) on a large proportion of their B cells. Injection of deaggregated human IgG caused a specific deletion of those B cells that express an intact IgM RF on their cell surface. The degree of RF B cell deletion was proportional to the reduction in the proliferative response of splenocytes to antigen (aggregated human IgG), or to F(ab')2 fragments of anti-human IgM antibodies. Control experiments showed that IgG administration had little effect on the numbers of mouse Ig-bearing cells or their ability to proliferate to a nonspecific mitogen. Thus, the effects of IgG on the human IgM RF B cell are antigen specific and are not due to nonspecific toxic effects of the human IgG preparation. These experiments demonstrate that peripheral exposure to IgG induces deletion of reactive B cells, without any evidence for anergy, and differ from data obtained by other investigators studying tolerance to soluble protein antigens. The results imply that human Igs have distinct properties as soluble antigens, and that peripheral nonresponsiveness to IgG may be due to lymphocyte deletion.

Animals↗
PubMed2006

Ocular autoimmunity: the price of privilege?

The eye is the prototypic immune-privileged organ. Its antigens were once believed to be expressed exclusively in the eye, which resides behind an efficient blood-organ barrier, and were believed to be unknown to the immune system. Self-tolerance to ocular components was therefore believed to be based not on immune tolerance but on immune ignorance. It is now known that the relationship between the immune system and the eye is much more complex. On the one hand, immune privilege is now known to involve not only sequestration but also active mechanisms that (i) inhibit innate and adaptive immune processes within the eye and (ii) shape the response that develops systemically to antigens released from the eye. On the other hand, retinal antigens are found in the thymus and have been shown to shape the eye-specific T-cell repertoire. However, thymic elimination of self-reactive T cells is incomplete, and such 'escapee' T cells are tolerized in the periphery as they recirculate through the body by encounter with self-antigen in healthy tissues. Due to the relative inaccessibility of the healthy eye to the immune system, peripheral tolerance mechanisms may not operate efficiently for ocular antigens, leaving a weak link in the homeostasis of tolerance. The case shall be made that although immune privilege protects vision by keeping the immune system at bay, a potential for developing destructive anti-retinal autoimmunity may be the price for the day-to-day protection afforded by immune privilege against inflammatory insults.

Animals↗
PubMed2006

Induction of tolerance in type 1 diabetes via both CD4+CD25+ T regulatory cells and T regulatory type 1 cells.

Success in developing novel therapies to recommence self-tolerance in autoimmunity depends on the induction of T regulatory (Tr) cells. Here, we report that rapamycin combined with interleukin (IL)-10 efficiently blocks type 1 diabetes development and induces long-term immunotolerance in the absence of chronic immunosuppression in nonobese diabetic (NOD) mice. Rapamycin mediates accumulation in the pancreas of suppressive CD4(+)CD25(+)FoxP3(+) Tr cells, which prevent diabetes. IL-10 induces Tr type 1 (Tr1) cells, which reside in the spleen and prevent migration of diabetogenic T-cells to the draining lymph nodes. These two Tr cell subsets act in concert to control diabetogenic T-cells that are still present in long-term tolerant mice. Rapamycin plus IL-10 treatment, promoting distinct subsets of Tr cells, may constitute a novel and potent tolerance-inducing protocol for immune-mediated diseases.

Adoptive Transfer↗
PubMed2005

T cell tolerance induced by cross-reactive TCR ligands can be broken by superagonist resulting in anti-inflammatory T cell cytokine production.

Cross-reactive activation of potentially autoreactive T cells by high-affinity nonself ligands may be important in breaking self-tolerance in autoimmunity. In a mouse transgenic for a cross-reactive TCR, we have previously shown that a hyper-stimulating altered peptide ligand, L144, induced unresponsiveness to the self peptide, proteolipid protein 139-151. In this study, we demonstrate that a superagonist ligand can break T cell tolerance induced by the lower affinity cognate Ag. T cells tolerant to the cognate ligand, Q144, responded to superagonist, L144, by proliferation and the production of mainly IL-4 and IL-10 in vitro. In contrast, T cells that were tolerized to the superagonist were unable to respond to any peptide that cross-reacted with the transgenic TCR. Low-dose immunization with the superagonist L144 was able to break tolerance to the cognate ligand in vivo and resulted in a blunted proliferative response with production of Th2 cytokines.

Animals↗