T-cell vaccination: from basics to the clinic.
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Animals↗
Biomedical subjects
E Sercarz
Publications and source records attributed to E Sercarz.
An integrative model of regulation centered on recognition of TCR peptide/MHC complexes.
We have described a T-cell receptor (TCR)-centered model of immune regulation, in which MHC/TCR peptide complexes provide for the activation of regulatory T cells and likewise act as their target structures. In this model, the disease-causing effectors are TCR Vbeta8.2+ and each of the required CD4 and CD8 regulatory T-cell populations are specific for different conserved regions of the Vbeta8.2 chain, in the appropriate MHC context. We have characterized the dominance, the dynamics as well as the TCR usage of both effector and regulatory T cells. We have begun to characterize the essential elements of the regulatory program, including the mechanism of interaction among effector and regulatory T-cell populations. Principles learned in this model have important implications for immune regulation in general.
Animals↗
Induction of a type 1 regulatory CD4 T cell response following V beta 8.2 DNA vaccination results in immune deviation and protection from experimental autoimmune encephalomyelitis.
DNA vaccination has been used to generate effective cellular as well as humoral immunity against target antigens. Here we have investigated the induction and involvement of regulatory T cell (T(reg)) responses in mediating prevention of experimental autoimmune encephalomyelitis (EAE), following vaccination with plasmid DNA encoding the TCR V(beta)8.2 chain predominantly displayed on disease-causing lymphocytes. Vaccination with DNA encoding the wild-type TCR results in priming of type 1 CD4 T(reg) and skewing of the global response to myelin basic protein in a T(h)2 direction, leading to significant protection from disease. In contrast, vaccination with mutant DNA encoding altered residues critically involved in recognition by the T(reg) results in priming of a type 2 regulatory response which fails to mediate immune deviation or protection from EAE. Control mice immunized with DNA, encoding TCR with changes at an irrelevant site, were protected from antigen-induced disease. Furthermore, protection can be transferred into naive recipients with CD4 T(reg) from wild-type DNA-immunized mice but not from animals vaccinated with the mutant DNA. These data suggest that vaccination with plasmid DNA encoding one or multiple V(beta) genes can be exploited to enhance natural regulatory responses for intervention in autoimmune conditions.
Animals↗
Report from the 1st International NOD Mouse T-Cell Workshop and the follow-up mini-workshop.
A workshop on autoreactive T-cell responses in NOD mice was held to optimize autoreactive T-cell detection methodologies. Using different proliferation assay protocols, 1 of the 11 participating laboratories detected spontaneous T-cell responses to GAD(524-543) and insulin(9-23) in their NOD mice. Two other laboratories were able to detect autoreactive responses when using enzyme-linked immunospot assay (ELISPOT) and enzyme-linked immunosorbent assay (ELISA) analysis of cytokines in culture supernatants, suggesting that these assays provided greater sensitivity. To address the divergent findings, a follow-up mini-workshop tested NOD mice from four different colonies side-by-side for T-cell proliferative responses to an expanded panel of autoantigens, using the protocol that had enabled detection of responses in the 1st International NOD Mouse T-Cell Workshop. Under these assay conditions, 16 of 16 NOD mice displayed proliferative responses to whole GAD65, 13 of 16 to GAD(524-543), 9 of 16 to GAD(217-236), 7 of 16 to insulin(9-23), and 5 of 16 to HSP277. Thus, spontaneous proliferative T-cell responses can be consistently detected to some beta-cell autoantigens and peptides thereof. Overall, the results suggest that more sensitive assays (e.g., ELISPOT, ELISA analysis of cytokines in supernatants, or tetramer staining) may be preferred for the detection of autoreactive T-cells.
Animals↗
Distinct levels of regulation in organ-specific autoimmune diseases.
Immune regulatory interactions have been largely attributed to antagonistic T helper cell subsets whose cytokines are mutually inhibitory (Th1 vs. Th2). Here we emphasize two additional levels of regulation: the first involves the recognition of portions of antigen receptors of effector T cells, resulting in the induction of both CD4 and CD8 regulatory populations, capable of diminishing the responses by the pathogenic effector itself. The second includes a collection of cell populations found constitutively in all individuals whose specificity for antigen, if any, is being currently investigated. These two additional types of interaction involve cells belonging to a functional regulatory subset and include contributions from both innate and adaptive mechanisms of immune regulation. The answers to many quandaries in autoimmune disease may be sought by seeking to engage these lesser-understood regulatory populations.
Animals↗
Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells.
Autoimmune diseases can result from the breakdown of regulation and subsequent activation of self-antigenic determinant-reactive T cells. During the evolution of the autoimmune response to myelin basic protein (MBP) in B10.PL mice, several distinct T cell populations expand: the effectors mediating experimental autoimmune encephalomyelitis (EAE) are MBP-reactive, CD4+, and predominantly TCR Vbeta8.2+; in addition, at least two regulatory populations can be detected--one comprised of Vbeta14+ CD4 T cells, reactive to a framework region 3 determinant on the Vbeta8.2 chain, and a second that is CD8+ and reactive to another Vbeta8.2 determinant. The combined action of these two regulatory cell types controls disease-causing effectors, resulting in spontaneous recovery from disease. In this report, we reveal that the cytokine secretion pattern of TCR peptide-specific regulatory CD4 T cells can profoundly influence whether a type 1 or type 2 population predominates among MBP-specific CD4 effectors. The priming of type 1 regulatory T cells results in deviation of the Ag-specific effector T cell population in a type 2 direction and protection from disease. In contrast, induction of type 2 regulatory T cells results in exacerbation of EAE, poor recovery, and an increased frequency of type 1 effectors. Thus, the encephalitogenic potential of the MBP-reactive effector population is crucially and dominantly influenced by the cytokine secretion phenotype of regulatory CD4 T cells. These findings have important implications in understanding peripheral tolerance to self-Ags as well as in the design of TCR-based therapeutic approaches.
Administration, Intranasal↗
In vivo priming of T cells against cryptic determinants by dendritic cells exposed to interleukin 6 and native antigen.
T cells recognizing poorly displayed self determinants escape tolerance mechanisms and persist in the adult repertoire. The process by which these T cells are primed is not clear, but once activated, they can cause autoimmunity. Here, we show that dendritic cells treated with interleukin 6 (IL-6) process and present determinants from a model native antigen in a qualitatively altered hierarchy, activating T cells in vitro and in vivo against determinants that were previously cryptic because of poor display. IL-6 does not induce conventional maturation of dendritic cells but alters the pH of peripheral, early endosomal compartments and renders the cells more susceptible to killing by chloroquine. Acidification of endosomes by ouabain mimics the effect of IL-6 and allows processing of the same cryptic determinant. These results suggest that cytokines such as IL-6 could initiate and help to propagate an autoimmune disease process by differentiating dendritic cells into a state distinct from that induced by normal maturation.
Animals↗
T cell vaccination in experimental autoimmune encephalomyelitis: a mathematical model.
T cell vaccination (TCV) is a method to induce resistance to autoimmune diseases by priming the immune system with autoreactive T cells. This priming evokes an anti-idiotypic regulatory T cell response to the receptors on the autoreactive T cells. Hence resistance is induced. To prevent the inoculated autoreactive cells from inducing autoimmunity, cells are given in a subpathogenic dose or in an attenuated form. We developed a mathematical model to study how the interactions between autoreactive T cells, self epitopes, and regulatory cells can explain TCV. The model is based on detailed data on experimental autoimmune encephalomyelitis, but can be generalized to other autoimmune diseases. We show that all of the phenomena collectively described as TCV occur quite naturally in systems where autoreactive T cells can be controlled by anti-idiotypic regulatory T cells. The essential assumption that we make is that TCV generally involves self epitopes for which T cell tolerance is incomplete. The model predicts a qualitative difference between the two vaccination methods: vaccination with normal autoreactive cells should give rise to a steady state of long lasting protection, whereas vaccination with attenuated cells should only confer transient resistance. Moreover, the model shows how autoimmune relapses can occur naturally without the involvement of T cells arising due to determinant spreading.
Animals↗
Tolerance and determinant hierarchy.
The overall T cell response to a multideterminant antigen consists of the sum of responses to a limited number of different determinants on the protein. Antigen-presenting cells (APCs) are crucial in delimiting the determinants on the protein to which a response will be mounted. This influence is apparent at two levels. First, the determinants that are generated and displayed by APCs in the thymus are pivotal in shaping the T cell repertoire that will be available for responding to antigen determinants in the periphery. Second, antigen processing affects the selection of determinants that become displayed by the various peripheral APC populations that are involved in inducing and promoting a T cell response. We have studied the effect of the display hierarchy on tolerance induction to individual determinants in transgenic mice expressing different serum levels of hen egg lysozyme. We have also analysed aspects of the processing machinery that contribute to shaping the hierarchy of determinant display on MHC class II molecules: proteolysis and reduction of disulfide bonds.
Amino Acids, Diamino↗
Recombinant T cell receptor molecules can prevent and reverse experimental autoimmune encephalomyelitis: dose effects and involvement of both CD4 and CD8 T cells.
Autoimmune diseases are often characterized by spontaneous remission followed by relapses. Although the mechanism(s) controlling pathogenic self-reactive T cells are not fully understood, recent data in experimental autoimmune encephalomyelitis (EAE), a prototype for CD4 T cell-mediated autoimmune diseases, indicate that spontaneous recovery is mediated by regulatory T cells (Treg) specific for peptides derived from the beta-chain of the TCR. Here we have tested whether recombinant single-chain TCRs (scTCRs) containing Vbeta domains can be used as vaccines for efficient priming of Treg. A single injection of mice with these recombinant proteins leads to efficient in vivo priming of Treg and almost complete protection from Ag-induced EAE. Significantly, administration of scTCRs during ongoing disease at a 10-fold lower dose than that required for prophylactic treatment also reverses established EAE. However, if a higher dose of scTCR is administered during ongoing disease, paralytic symptoms become exacerbated and the majority of treated animals die from severe and chronic EAE. Furthermore, we demonstrate that regulatory determinants are processed and presented from scTCRs resulting in the recruitment of both CD4 and CD8 regulatory T cells which are required for efficient regulation induced by scTCR. Reversal of established disease following an optimum dose of recombinant TCRs suggests that proteins expressing appropriate Vbeta domains could be used for the treatment of a variety of T cell-mediated pathologic conditions.
Animals↗
Regulatory T cells specific for the same framework 3 region of the Vbeta8.2 chain are involved in the control of collagen II-induced arthritis and experimental autoimmune encephalomyelitis.
Recent evidence indicates that chronic autoimmune disease can result from breakdown of regulation and subsequent activation of self-reactive T cells. In many murine autoimmune disease systems and in the Lewis rat, antigen-specific T cells utilizing the T cell receptor (TCR) Vbeta8.2 gene segment play a major role. In the myelin basic protein-induced experimental autoimmune encephalomyelitis (EAE) model in H-2(u) mice, we had shown that T cells recognizing a peptide determinant within the framework 3 region of the Vbeta8.2 chain have a critical role in influencing the course of the disease. Here, we report experiments in another disease system, collagen II (CII)-induced arthritis (CIA) in DBA/1LacJ (H-2(q)) mice, indicating a remarkably parallel control circuit to that found for EAE. A critical role is played by CII-specific Vbeta8.2-bearing T cells in the CIA system, which we have confirmed. Animals treated with the superantigen SEB before CII administration are significantly protected from CIA. Next, we tested the ability of peptides encompassing the entire Vbeta8.2 chain to induce proliferative responses. Only TCR peptide B5 (amino acids 76-101), a regulatory peptide in EAE, induced proliferation. B5 was then used to vaccinate DBA/1LacJ mice and was shown to reduce greatly the severity and incidence of CIA as measured by joint inflammation or histology. Furthermore, similar protection was found when B5 was administered after CII immunization. It was shown that there is physiological induction of a proliferative response to B5 during CIA and that the determinant within B5 is produced from a single chain TCR construct containing the entire Vbeta8.2 chain. Finally, the regulation of CIA is discussed in the context of other experimental autoimmune diseases, especially EAE, with emphasis on what appear to be strikingly common mechanisms.
Amino Acid Sequence↗
Inactivation of T cell receptor peptide-specific CD4 regulatory T cells induces chronic experimental autoimmune encephalomyelitis (EAE).
T cell receptor (TCR)-recognizing regulatory cells, induced after vaccination with self-reactive T cells or TCR peptides, have been shown to prevent autoimmunity. We have asked whether this regulation is involved in the maintenance of peripheral tolerance to myelin basic protein (MBP) in an autoimmune disease model, experimental autoimmune encephalomyelitis (EAE). Antigen-induced EAE in (SJL x B10.PL)F1 mice is transient in that most animals recover permanently from the disease. Most of the initial encephalitogenic T cells recognize MBP Ac1-9 and predominantly use the TCR V beta 8.2 gene segment. In mice recovering from MBP-induced EAE, regulatory CD4+ T cells (Treg) specific for a single immunodominant TCR peptide B5 (76-101) from framework region 3 of the V beta 8.2 chain, become primed. We have earlier shown that cloned B5-reactive Treg can specifically downregulate responses to Ac1-9 and also protect mice from EAE. These CD4 Treg clones predominantly use the TCR V beta 14 or V beta 3 gene segments. Here we have directly tested whether deletion/blocking of the Treg from the peripheral repertoire affects the spontaneous recovery from EAE. Treatment of F1 mice with appropriate V beta-specific monoclonal antibodies resulted in an increase in the severity and duration of the disease; even relapses were seen in one-third to one-half of the Treg-deleted mice. Interestingly, chronic disease in treated mice appears to be due to the presence of Ac1-9-specific T cells. Thus, once self-tolerance to MBP is broken by immunization with the antigen in strong adjuvant, TCR peptide-specific CD4 Treg cells participate in reestablishing peripheral tolerance. Thus, a failure to generate Treg may be implicated in chronic autoimmune conditions.
Adoptive Transfer↗
A truncated T cell receptor repertoire reveals underlying immunogenicity of an antigenic determinant.
Induction of T cell responses to an antigenic peptide that is known to bind a major histocompatibility complex molecule is a function of either the T cell receptor (TCR) repertoire or regulatory influences by CD8 or CD4 regulatory T cells. We have tested the hypothesis that a lack of 10 TCR V beta gene segments in V beta a mice may result in an incomplete repertoire of regulatory T cells involved in maintaining peripheral tolerance. Such a hole in the repertoire of regulatory cells could result in expression of T cell responses to antigenic determinants that normally remain undetected in mice with a wild-type repertoire of TCR V beta gene segments. We show here that H-2d mice respond to the peptide 74-96 of hen egg-white lysozyme (HEL) when they are of V beta a haplotype at their TCR locus. The wild-type (V beta b) H-2d mice with their complete set of 20 TCR V beta gene segments fail to respond to HEL 74-96. The 74-96-specific T cell responsiveness was revealed in the wild-type (V beta b) mice when they were treated in vivo with anti-CD8 antibody, implicating the existence of regulatory cells that prevent expression of T cell responses specific for peptide 74-96. This is a demonstration that holes in the regulatory T cell repertoire can, in certain circumstances, become beneficial to the host, for example, in susceptibility against pathogens.
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Dysregulation of potentially pathogenic self reactivity is crucial for the manifestation of clinical autoimmunity.
During the evolution of the autoimmune response to myelin basic protein (MBP), at least two distinct lymphocyte populations arise, one that is specific for determinants within the protein antigen and another that is specific for the receptors displayed by the antigen-specific lymphocytes themselves. The T-cell receptor (TCR)-specific lymphocytes appear to oppose the action of the pathogenic effector cells, which predominantly utilize the TCR V beta 8.2 gene segment. We will discuss our work suggesting that both CD4 and CD8 cells specific for different TCR determinants on the V beta 8.2 chain are involved in the regulation of MBP-specific CD4 T cells mediating experimental autoimmune encephalomyelitis. We suggest that a crucial balance between the effectors and regulators is decisive for the clinical manifestation of autoimmunity.
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Immune deviation during the induction of tolerance by way of nasal installation: nasal installation itself can induce Th-2 responses and exacerbation of disease.
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Administration, Intranasal↗
Genetic vaccination: the advantages of going naked.
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Animals↗
Major histocompatibility complex binding affinity of an antigenic determinant is crucial for the differential secretion of interleukin 4/5 or interferon gamma by T cells.
Differential activation of CD4+ T-cell precursors in vivo leads to the development of effectors with unique patterns of lymphokine secretion. To investigate whether the differential pattern of lymphokine secretion is influenced by factors associated with either the display and/or recognition of the ligand, we have used a set of ligands with various class II binding affinities but unchanged T-cell specificity. The ligand that exhibited approximately 10,000-fold higher binding to I-Au considerably increased the frequency of interferon gamma-producing but not interleukin (IL) 4- or IL-5-secreting cells in vivo. Using an established ligand-specific, CD4+ T-cell clone secreting only IL-4, we also demonstrated that stimulation with the highest affinity ligand resulted in interferon gamma production in vitro. In contrast, ligands that demonstrated relatively lower class II binding induced only IL-4 secretion. These data suggest that the major histocompatibility complex binding affinity of antigenic determinants, leading to differential interactions at the T cell-antigen-presenting cell interface, can be crucial for the differential development of cytokine patterns in T cells.
Amino Acid Sequence↗
Immunodominant framework region 3 peptide from TCR V beta 8.2 chain controls murine experimental autoimmune encephalomyelitis.
Previous work has demonstrated the existence of regulatory circuitry that controls response to the dominant determinant Ac1-9 of myelin basic protein (MBP) which is highly restricted in TCR V gene usage to V beta 8.2 and V alpha 2.3. In particular, a CD4+ V beta 14+ regulatory T cell was shown to be a vital component of this circuit. In our work presented here, the peptide specificity of the response to V beta 8.2 peptides was examined. Five overlapping peptides, B1 through B5, were studied for their ability to induce a proliferative response: B2 (21-50), B4 (61-90), and B5 (76-101) each had this capacity in the B10.PL or (SJL x B10.PL)F1 mice. The determinant within the TCR peptide B5 appears dominant, whereas determinants within the B2 and B4 peptides are physiologically cryptic. Furthermore, only B5 could down-regulate the response to MBP Ac1-9 and significantly protect mice from MBP- or Ac1-9-induced EAE, whereas B2 or B4 treatment had no significant effect. Treatment of mice with B5 did not result in generalized deletion or inactivation of V beta 8.2+ T cells. The core residues of the B5 determinant lie within framework region 3 of the V beta 8.2 chain and do not include residues from the joining CDR3 region. Response to B5 was restricted by the I-Au MHC molecule. Furthermore, B5 only induced responses in mice with certain MHC alleles. It is evident that by specifically down-regulating the initial dominant response to Ac1-9, Ag-induced disease can be prevented. These data have implications for understanding induction of TCR-based regulation, as well as relevance to possible therapeutic approaches for oligoclonal responses in human autoimmune diseases.
Amino Acid Sequence↗