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Stephen M Anderton

Publications and source records attributed to Stephen M Anderton.

18 recordsLinked to original sources
PubMed2006

Distinct T cell recognition of naturally processed and cryptic epitopes within the immunodominant 35-55 region of myelin oligodendrocyte glycoprotein.

We have assessed the complexity in T cell recognition of the immunodominant 35-55 region of myelin oligodendrocyte glycoprotein (MOG) in C57BL/6 mice. Immunization with the p35-55 peptide generated two types of T cell, recognizing either a cryptic, or a naturally-processed epitope. Clear differences in the recognition of residues within a core sequence of 40-48 were observed. The majority of the p35-55-reactive repertoire in vivo appeared responsive to the intact autoantigen, supporting the notion of a failure of central tolerance to this region of MOG. Our data also provide a basis for exploring the requirements for antigen processing of MOG.

Amino Acid Sequence↗
PubMed2006

Avoiding autoimmune disease--T cells know their limits.

The molecular mimicry theory has become a dominant paradigm to explain the triggering of autoaggressive T lymphocytes. The basis of the theory is that an immune response is triggered by non-self during infection and subsequent cross-reactive T-cell recognition of a similar self antigen provokes an inflammatory lesion in the target organ. It is clear that we all harbour autoreactive T cells and that T-cell receptor (TCR) cross-reactivity is extensive. Here, I argue that the immune system has evolved mechanisms to limit the risk of an autoaggressive response. Importantly, the strength of TCR stimulation provided by self and non-self antigens will usually differ. Evidence points to a model in which the three pillars of immune tolerance (deletion, anergy-adaptation and regulation) act to limit autoimmune disease from molecular mimicry.

Adaptation, Biological↗
PubMed2006

Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)-specific T cell repertoires in MOG-expressing mice.

Experimental autoimmune encephalomyelitis, an experimental murine model for multiple sclerosis, is induced by stimulation of myelin-specific T lymphocytes. Myelin oligodendrocyte glycoprotein (MOG), a minor component of myelin proteins, is a potent autoantigen which contributes extensively to the anti-myelin response. In the present work, immunoscope analyses and sequencing of the oligoclonal expansions revealed anti-MOG Valpha and Vbeta public repertoires in lymphocytes infiltrating the CNS of wild-type (WT) mice. Moreover, a subset of CNS-infiltrating CD4+ T lymphocytes bearing the public Vbeta8.2 segment have an inflammatory phenotype strongly suggesting that it is encephalitogenic. We then observed that, in lymph node cells of MOG-deficient and WT animals, the Valpha and Vbeta public repertoires expressed by MOG-specific T cells are identical in both strains of mice and correspond to those found in the CNS of WT animals. These findings indicate that the MOG immunodominant determinant is unable to induce tolerance by deletion, and public anti-MOG T cell repertoires are selected for, regardless of the presence of MOG in the thymus and peripheral organs.

Animals↗
PubMed2006

Circumventing tolerance at the T cell or the antigen-presenting cell surface: antibodies that ligate CD40 and OX40 have different effects.

An adjuvant can be defined as an agent that non-specifically promotes the immune response to an accompanying antigen. Ligation of CD40 on the surface of the antigen-presenting cell leads to upregulation of OX40 ligand which, in turn, ligates OX40 on the activated T cell resulting in prolonged T cell proliferation/survival, boosting the immune response. Thus agonistic anti-CD40 and anti-OX40 might be viewed as "adjuvant antibodies" and have been shown in diverse experimental systems to either boost immune responses or prevent the establishment of immunological tolerance. Here we describe that both these antibodies are able to prevent the induction of tolerance induced using soluble peptide antigen. However, unlike lipopolysaccharide, they are not sufficient to convert tolerance to immunity (i.e. they are not true adjuvants in this system). Using mice that are prone to either Th1 or Th2 immunity under identical immunization conditions, we show that the effects of anti-OX40 are quantitative -- boosting whichever response is dominant. In contrast, anti-CD40 boosts Th1 immunity and converts a Th2 response to Th1. We conclude that, although these two antibodies seem to impact on the same molecular pathway of costimulation to prevent tolerance, their effects are qualitatively distinct and their use cannot be viewed as interchangeable.

Adjuvants, Immunologic↗
PubMed2006

Immunological tolerance using synthetic peptides--basic mechanisms and clinical application.

Dysregulation of T lymphocyte function underpins the development of autoimmune and allergic diseases. These autoantigen-, or allergen-reactive pathogenic T cells are rare within the entire immune repertoire and it is therefore desirable to develop more specific therapies than are currently in use to directly target these cells and avoid adverse side effects. The obvious approach is to use the antigens that are recognized to impose a state of T cell tolerance. T cells recognize antigens as peptide fragments and we can therefore produce the relevant antigens as synthetic peptides. It has been known for many years that the decision of the T cell to mount a productive response (immunity) or to remain silent (tolerance) is controlled by the form in which the antigen is administered. Antigen with adjuvant leads to immunity, whereas soluble antigen without adjuvant leads to tolerance. This paradigm has been used successfully to induce tolerance with soluble peptides, preventing several animal models of autoimmune and allergic disease. These findings obviously have exciting potential for translation to human diseases. However, the basic immune mechanisms that lead to tolerance versus immunity are only beginning to be unravelled. The "effector" phase of tolerance also remains controversial with evidence for T cell death, anergy and the development of immunoregulatory function. This latter possibility of specifically generating autoantigen- or allergen-reactive regulatory T cells is particularly attractive. Here we review recent advances in our understanding of the requirements for tolerance induction and the potential for establishing dominant immune-regulation with peptide therapy.

Animals↗
PubMed2005

CD4+CD25+ regulatory T cells limit the risk of autoimmune disease arising from T cell receptor crossreactivity.

The molecular-mimicry theory proposes that immune crossreactivity between microbial and self-antigen is the initiating event in the activation of autoaggressive immune responses leading to autoimmune disease. In support of this possibility, it is now accepted that T cell recognition of antigen is highly degenerate. However, it is to be expected that the immune system would have evolved mechanisms to counter such a potential danger. We studied the influence of CD4(+)CD25(+) regulatory T cells (Treg) on the ability of suboptimal T cell receptor ligands to provoke autoimmunity. By using CD4(+) T cell-driven experimental autoimmune encephalomyelitis as a model, it was found that depletion of CD4(+)CD25(+)Foxp3(+) Treg allowed pathology to develop in response to suboptimal T cell stimulation. These data demonstrate the importance of Treg in raising the threshold of triggering of autoreactive T cell responses, thus limiting the risk of autoimmune disease due to molecular mimicry.

Animals↗
PubMed2005

Cytokines in the induction and resolution of experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis is the prototypic T cell-mediated autoimmune disease model. Classically, this disease was viewed in terms of type 1 versus type 2 immunity: the type 1 cytokines IFNgamma and TNFalpha promoting disease, whereas an IL-4-dominated, type 2 response was protective. However, studies in knockout mice do not support this paradigm. More recent data point to important roles for IL-23 and IL-17 (rather than IL-12 and IFNgamma) in the establishment and persistence of the inflammatory lesion. IL-10 appears to be the dominant cytokine mediating recovery. The source of IL-10 includes B cells (most probably in the peripheral lymphoid organs). However, the key IL-10-producing cell within the central nervous system is a CD4+CD25+ T cell population that has regulatory function and is critical to resolution of the disease.

Animals↗
PubMed2005

Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system.

Immune regulation of autoimmune disease can function at two sites: at the secondary lymphoid organs or in the target organ itself. In this study, we investigated the natural resolution of autoimmune pathology within the CNS using murine experimental autoimmune encephalomyelitis (EAE). Recovery correlates with the accumulation of IL-10-producing CD4+CD25+ T cells within the CNS. These CD4+CD25+ cells represent as many as one in three of CD4+ cells in the CNS during recovery, they are FoxP3+ and express other markers associated with regulatory cells (CTLA-4, GITR, and alpha(E)beta7), and they have regulatory function ex vivo. Depletion of CD25+ cells inhibits the natural recovery from EAE. Also, depletion of CD25+ cells after recovery removes the resistance to reinduction of EAE observed in this model. Furthermore, passive transfer of CNS-derived CD4+CD25+ cells in low numbers provides protection from EAE in recipient mice. These are the first data demonstrating the direct involvement of CD4+CD25+ regulatory T cells in the natural resolution of autoimmune disease within the target organ.

Amino Acid Sequence↗
PubMed2005

Fas-mediated death and sensory adaptation limit the pathogenic potential of autoreactive T cells after strong antigenic stimulation.

The ability of autoreactive T cells to induce autoimmune pathology is dependent on their ability to respond to the level of autoantigen presented in the target organ. Emerging evidence suggests that at the population level, T cell sensitivity for self can be reduced by deletion of those cells bearing high-affinity T cell receptors (TCRs) or by sensory adaptation of individual cells. Here, we have investigated the mechanisms that prevent the induction of experimental autoimmune encephalomyelitis (EAE) when myelin basic protein (MBP)-reactive T cells are exposed to a strong, antigenic stimulus. Stimulation of MBP-reactive TCR transgenic T cells with a superagonist peptide led to extensive activation-induced cell death (AICD) through Fas signaling. Using T cells lacking Fas, we found that disruption of this deletional mechanism only partially increased EAE in response to superagonist, failing to restore susceptibility to the level found in response to the wild-type MBP peptide. A significant fraction of the MBP-reactive T cells was able to avoid AICD in response to superagonist, but these cells had a reduced sensitivity for an antigen that correlated with elevated levels of CD5. Therefore, when TCR affinity is fixed, autoreactive T cell sensitivity can be shifted to below a threshold for harm by a combination of AICD and sensory adaptation.

Adaptation, Physiological↗
PubMed2005

Kinetics of costimulatory molecule expression by T cells and dendritic cells during the induction of tolerance versus immunity in vivo.

Steady-state dendritic cells (DC) present peptide-MHC complexes to T cells in a tolerogenic manner, presumably because of deficient costimulation. However, it is clear that the path to tolerance involves initial T cell activation, suggesting that the deficit may lie in late-acting costimulatory molecules. With this in mind we have investigated the kinetics of expression of several costimulatory pairs on DC and OVA-reactive T cells after i.v. injection of mice with peptide and LPS (immunity), or peptide alone (tolerance). We find that T cells up-regulate CD154, OX40, RANKL and PD-1 whether they are destined for tolerance or immunity, although there are some differences in the levels and length of expression. In contrast, when analyzing DC, we found that up-regulation of CD80, CD86, CD40, RANK and PDL-1 occurred only when peptide was co-administered with LPS. These data give a picture of the T cell looking for costimulatory cues that are not forthcoming when pMHC is presented by steady-state DC, leading to tolerance. However, we did see a strong and rapid up-regulation of RANKL on T cells that occurred specifically when peptide was given in the absence of LPS, suggesting a possible positive signal influencing the decision between tolerance and immunity.

Animals↗
PubMed2004

Systemic administration of antigen-loaded CD40-deficient dendritic cells mimics soluble antigen administration.

The decision to mount a T cell response to antigen (Ag) is dependent on the cellular context in which the Ag is presented. Activated dendritic cells (DC) are potent stimulators of immune responses, an ability which is linked to their high expression of several costimulatory molecules. In contrast, resting DC have been implicated in the generation of self tolerance, presumably due to their reduced costimulatory capacity. However, the precise molecular basis for the choice between Ag-induced immunity and unresponsiveness remains unclear. We show here that CD40 plays an important rolein this decision. Systemic administration of Ag-loaded, CD40-deficient DC failed to induce a productive primary T cell expansion and rendered mice relatively unresponsive to subsequent immunization with Ag in adjuvant. Using a TCR-transgenic T cell transfer system, we found that CD40(-/-) DC triggered an initial T cell activation that could not be sustained, resulting in loss of Ag-reactive T cells and reduced cytokine production by those T cells that did persist. Furthermore, administration of CD40(-/-) DC that had been loaded with a central nervous system autoantigen was found to protect mice from autoimmune pathology. These data implicate the CD40:CD40L interaction as a key checkpoint in the development of T cell immunity rather than tolerance.

Animals↗
PubMed2004

Post-translational modifications of self antigens: implications for autoimmunity.

Alterations in amino acid sequence can generate neo-epitopes from self proteins, causing autoaggressive immune attack. There is a range of possible post-translational modifications (PTMs) of mammalian proteins that can allow immune recognition of neo-self epitopes. These effects can vary from overt increase in affinity of MHC or T-cell receptor binding, to more subtle effects on the activity of proteolytic enzymes involved in antigen processing. Furthermore, intriguing insights into how the complex interactions between inflammation, enzyme activity and protein modification can direct self recognition are beginning to be unearthed.

Animals↗
PubMed2004

Activation thresholds determine susceptibility to peptide-induced tolerance in a heterogeneous myelin-reactive T cell repertoire.

Altered peptide ligands (APL) with increased MHC-binding properties are highly effective at inducing T cell tolerance after systemic administration in soluble form, preventing experimental autoimmune encephalomyelitis (EAE) induced with the myelin basic protein (MBP) Ac1-9 peptide. We have previously described a diverse Ac1-9-reactive T cell repertoire with differing TCR affinities. A remaining question is what proportion of this repertoire is silenced by peptide therapy? Here, we show that the sensitivity of a T cell to peptide-induced tolerance is related to its avidity for native Ac1-9. These data provide new evidence that self-reactive T cells bearing low-affinity TCRs are able to escape therapeutic induction of tolerance.

Animals↗
PubMed2002

B cells regulate autoimmunity by provision of IL-10.

To assess the importance of B cell control of T cell differentiation, we analyzed the course of the T helper type 1 (T(H)1)-driven disease experimental autoimmune encephalomyelitis in mice with an altered B cell compartment. We found that recovery was dependent on the presence of autoantigen-reactive B cells. B cells from recovered mice produced interleukin 10 (IL-10) in response to autoantigen. With a bone marrow chimeric system, we generated mice in which IL-10 deficiency was restricted to B cells but not T cells. In the absence of IL-10 production by B cells, the pro-inflammatory type 1 immune response persisted and mice did not recover. These data show that B cell-derived IL-10 plays a key role in controlling autoimmunity.

Animals↗
PubMed2002

Influence of a dominant cryptic epitope on autoimmune T cell tolerance.

The rules governing which T cells are inactivated during peptide-induced tolerance are unclear. Here we show that MBP(89-101) contains three overlapping but distinct T cell epitopes that are restricted by a single major histocompatibility complex (MHC) class II molecule. The dominant epitope is not processed from MBP and is not relevant to the induction of autoimmunity. Pathogenic T cells recognize two minor epitopes that are processed from MBP but are presented only poorly after exposure to MBP(89-101). Induction of immunological tolerance by MBP(89-101) therefore inactivates T cells that recognize the dominant epitope and disease-relevant T cells escape tolerance. The topology of the three epitopes implicates asparagine endopeptidase as the enzyme that controls recognition of this region of MBP. Our results highlight the need to use peptides that mimic the binding of processed antigen fragments to MHC molecules for successful modulation of disease-relevant T cells.

Amino Acid Sequence↗
PubMed2002

Cross-reactivity and T-cell receptor antagonism of myelin basic protein-reactive T cells is modulated by the activation state of the antigen presenting cell.

The peripheral T-cell population is educated to recognize a maximum of pathogen-derived epitopes while ignoring self-antigens. As the total number of T-cell clones is limited, each T-cell receptor (TCR) needs to be cross-reactive in order to achieve a wide repertoire. This opens the possibility for T cells to diverge from their defending role and induce auto-aggression by mistake. The factors involved in the initiation of such autoimmune responses remain to be fully understood. In an attempt to assess the role of antigen presenting cells (APC) in the triggering of autoimmunity, we studied the cross-reactivity of TCR transgenic Tg4 T cells, reactive to the Ac1-9 peptide of myelin basic protein (MBP). Using different APC populations and a range of peptide analogues of Ac1-9, we found that the activation of APC enhanced the cross-reactivity of Tg4 cells, and that this effect could be mimicked by resting APC supplemented with exogenous co-stimulation. Further, we observed that the inhibitory effect of an antagonist peptide of the Tg4 TCR was greatly reduced when activated APC were used. However, when co-stimulation was blocked, TCR antagonism was restored to its normal level. Our results show for the first time that the activation of naturally occurring APC, namely dendritic cells, B cells and macrophages, can modulate the reactivity of T cells, both in terms of cross-reactivity and TCR antagonism, and that this effect is most likely due to enhanced levels of co-stimulation.

Animals↗
PubMed2002

Selection and fine-tuning of the autoimmune T-cell repertoire.

The immune system must avoid aggressive T-cell responses against self-antigens. But, paradoxically, exposure to self-peptides seems to have an important role in positive selection in the thymus and the maintenance of a broad T-cell repertoire in the periphery. Recent experiments have highlighted situations that allow high-avidity self-reactive T cells to avoid negative selection in the thymus. Accumulating evidence indicates that other, non-deleting mechanisms control the avidity with which T cells recognize self-antigens--a phenomenon that is known as 'tuning'. This might maximize the peripheral T-cell repertoire by allowing the survival of T cells that can respond to self, but only at concentrations that are not normally reached in vivo.

Animals↗