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E Sercarz

Publications and source records attributed to E Sercarz.

At least 37 records · Page 2Linked to original sources
PubMed1995

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↗
PubMed1994

Holes in the T cell repertoire to myelin basic protein owing to the absence of the D beta 2-J beta 2 gene cluster: implications for T cell receptor recognition and autoimmunity.

Models of T cell recognition suggest that amino acid residues in the CDR3 region of the T cell receptor (TCR) alpha or beta chain directly contact the major histocompatibility complex-bound peptide, and thus are crucial for providing peptide specificity. T cells derived from B10.PL or PL/J mice of H-2u haplotype, use only D beta 2 and J beta 2 gene segments in the recognition of the dominant determinant, Ac1-9/Au, of myelin basic protein (MBP). New Zealand White (NZW) mice, with identical class II H-2u genes (I-A and I-E), carry an 8.8-kb deletion in their TCR beta chain locus encompassing D beta 2 and J beta 2 gene segments. How does this deletion of the crucial D beta 2-J beta 2 region in NZW mice influence specific responses to Ac1-9/Au as well as to other known Au or Eu determinants of MBP? We found that these mice respond very poorly to the dominant Ac1-9/Au and to the subdominant 31-50/Eu determinant in in vitro proliferation assays as well as in their in vivo capacity to induce experimental autoimmune encephalomyelitis. This loss of response is apparently owing to the absence of high avidity TCRs with essential CDR3 residues contributed by D beta 2 or J beta 2 gene segments. These data reveal constraints in the recognition of certain antigenic structures, and further support a TCR-recognition model in which CDR3 residues of the TCR alpha and beta chains constitute the antigenic peptide-binding sites on the TCR molecule. Implications for autoimmune manifestations contributed by NZW genes in (NZB x NZW)F1 disease are also discussed.

Animals↗
PubMed1993

Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease.

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

Animals↗
PubMed1993

A peptide derived from an autoantibody can stimulate T cells in the (NZB x NZW)F1 mouse model of systemic lupus erythematosus.

OBJECTIVE: To assess the ability of peptides derived from anti-DNA to stimulate syngeneic T lymphocytes and influence lupus in (NZB x NZW)F1 (NZB/W) mice. METHODS: We synthesized (by Geysen pin method) overlapping 12-mer peptides recapitulating the amino acid sequence of the VH region of a nephritogenic monoclonal IgG2a anti-DNA antibody (A6.1) from an NZB/W mouse. Splenic T cells were cultured with the peptides; multiple experiments assayed 12-mer and 16-mer peptides which contained a triple-base motif (KFKGK). We immunized 20-week-old NZB/W mice with the 12-mer and evaluated them for evidence of nephritis and for quantities of antibodies in plasma and glomeruli. RESULTS: Three clusters of peptides caused proliferation of spleen cells from young, nonimmunized mice. Both the 12-mer FYNQKFKGKATL and the 16-mer GDTFYNQKFKGKATLT peptides stimulated purified T cells. The KXKXK motif occurs in 15% of murine Ig VH (NBRF protein database), compared with 100% (6 of 6) of NZB/W anti-DNA monoclonal antibody. Immunization with the 12-mer peptide increased plasma levels of IgG, anti-DNA, and immune complexes, and levels of anti-DNA in glomeruli; nephritis was accelerated. CONCLUSION: NZB/W anti-DNA contain peptide sequences in their VH regions that stimulate self-T cells. At least one motif is frequent in NZB/W anti-DNA. If some activated T cells provide help, this mechanism may contribute to sustained up-regulation of autoantibodies in murine lupus.

Amino Acid Sequence↗
PubMed1993

Sympathetic regulation of T-helper cell function.

The role of sympathetic neurotransmission in regulation of T-cell function was examined in mice. After in vivo priming with a model protein antigen, hen egg white lysozyme (HEL), the specific proliferative recall response of lymph node cells (LNCs) was examined. The release of endogenous catecholamines by amphetamine (5 mg/kg, 45 min prior to sacrifice) markedly inhibited the proliferative response of LNCs. Combined alpha- and beta-adrenergic blockade (phentolamine, 1.0 mg/kg+propranolol, 2.5 mg/kg) prevented this effect of amphetamine on proliferation. In vitro, the alpha-adrenergic agonist phenylephrine, but not the beta-agonist isoproterenol, inhibited proliferation in a dose-dependent manner, up to 80%. The effect of phenylephrine was blocked by the alpha-adrenoceptor antagonist phentolamine. The effects of catecholamines appear to be mediated at the level of antigen processing/presentation: Amphetamine given prior to sacrifice inhibited interleukin 2 production when irradiated spleen cells were used to present HEL and HEL-related peptides to HEL-specific T-cell hybridomas. In summary, the sympathetic nervous system seems to inhibit antigen processing/presentation and, indirectly, T-helper responses.

Animals↗
PubMed1993

The involvement of antigen processing in determinant selection by class II MHC and its relationship to immunodominance.

The T cell response in vivo to many whole proteins is focused on a limited number of possible determinants which can be termed immunodominant. Antigen processing for class II antigen presentation appears to play a major role in this selective process. With experimental evidence accumulated in our laboratory as well as others, we review several possible mechanisms involved in antigen processing responsible for selective or differential determinant expression. In particular, we discuss the determinant capture model in which MHC class II molecules initially capture large antigen fragments, such that bound determinants are protected from proteolysis by the MHC molecules and eventually become dominant while the flanking determinants are trimmed away. Such flanking determinants therefore become subdominant or cryptic. This mechanism underlies the capturing role of MHC molecules in the physiological processing of antigens.

Animals↗
PubMed1992

Tolerance to a self-protein involves its immunodominant but does not involve its subdominant determinants.

We have produced transgenic mice expression hen egg-white lysozyme (HEL) under the control of a ubiquitous promoter, so that in transgenic animals, HEL is presumably present in the serum and thymus throughout the period of establishment of the T-cell repertoire. We show that HEL transgenic H-2d mice with HEL blood levels greater than 10 ng/ml are tolerant to HEL as well as to the immunodominant peptide 108-116. Thus, their T lymphocytes do not proliferate in response to the immunodominant peptide 108-116 after in vivo immunization with HEL or peptide 108-116. In contrast, in transgenic mice tolerant to HEL, the state of tolerance to subdominant peptides 1-18 and 74-96 appears variable and highly depended on HEL blood levels. Complete unresponsiveness is seen when HEL serum levels are high, and this unresponsiveness is reached at a lower HEL concentration for peptide 1-18 than for peptide 74-96. Thus, a hierarchy exists among the three peptides (108-116 much greater than 1-18 greater than 74-96) for induction of a response to HEL and for HEL tolerance induction in T cells specific for these peptides. Persistence in the periphery of autoreactive T cells recognizing subdominant peptides of self-proteins, as shown in this transgenic model, indicates that self-tolerance is limited to a subset of dominant self-peptides and suggests a role for T lymphocytes specific for subdominant determinants in autoimmunity.

Animals↗
PubMed1991

Limitations in plasticity of the T-cell receptor repertoire.

How constrained is T-cell recognition? Is a truncated T-cell receptor (TCR) repertoire, missing half of its V beta components (where V indicates variable), still broad enough to produce an antigen-specific T-cell response to all determinants? These questions can be answered for certain T-cell antigenic determinants whose response in the wild type is limited to specific gene segments. Our results show that mice with such a deletion in their TCR V beta genes (V beta truncated haplotype, Va beta) are unable to respond to two antigen determinants (sperm whale myoglobin 111-121/I-Ed and myelin basic protein 1-11/I-Au) whose response in the wild type is restricted to the missing V beta (V beta 8.2 in the case of 111-121/I-Ed and V beta 8.2 and V beta 13 in the case of 1-11/I-Au) gene segments. Fundamentally, this restriction could have been attributed to another aspect of immunodominance--that a favored TCR with high affinity would dominate the response, but in its absence, a hierarchy of T cells with lesser efficiency and expressing alternate TCR V genes could take over. However, from our experiments it has become evident that there is an absolute limit to the flexibility inherent in the TCR repertoire. Since it is clear that mouse populations have many ambient deletion ligands (such as self-superantigens) that can result in the loss of multiple V beta gene segments during normal T-cell development, these deletions can have serious consequences, such as unresponsiveness to the antigen as a whole--a hole in the repertoire--if a dominant determinant of that antigen normally shows restricted TCR V beta gene usage.

Animals↗
PubMed1991

The distinctive specificity of antigen-specific suppressor T cells.

Although suppressor T cells have been cloned in only a few instances, the existence of a functional cadre of T cells that acts to downregulate the immune response is well documented. In this review Eli Sercarz and Urszula Krzych describe studies on suppressor T-cell (TS-cell) specificity that provide some support for the conclusion that the TS cell is a distinctive cell type with an expressed repertoire that is different from that expressed by helper T (TH) cells. They go on to explore the interaction between cells recognizing TS-cell-inducing determinants (SDs) and TH-cell-inducing determinants (HDs), and their relationship to immunogenicity and Ir gene effects.

Amino Acid Sequence↗
PubMed1990

Does the presence of self-reactive T cells indicate the breakdown of tolerance?

There are many experimental systems in which autoreactive T cells can easily be demonstrated but where the host does not normally develop autoimmune disease. How do these animals avoid autoimmunity? Does the presence of these self-reactive cells indicate the failure of self-tolerance? To answer these questions it is necessary to consider how some T cells might escape tolerance induction and why they are not activated in the host. There are several different explanations which can be broadly placed into one of two categories. First, although autoreactive cells may be easily stimulated under experimental conditions, the requirements for activation and likewise deletion may not be met under physiological conditions. The self-antigen may be poorly presented by APC or sequestered in a particular body compartment; alternatively, these T cells may have low affinity receptors needing high levels of antigen. The second category is characterized by the need for immunoregulation. A random selection of T cells may escape clonal inactivation in the thymus but may be kept under constant suppression, which provides a fail-safe mechanism for deletional tolerance. In this review we will discuss these mechanisms and their possible importance in the prevention of autoimmunity.

Animals↗
PubMed1990

T cell dominance and the vaccine problem: modifying effects on immunogenicity by residues at a distance from the site of T cell recognition.

The design of the optimal T cell-inducing component of a vaccine requires consideration of events both at, and distant from, the T cell recognition site. This area is approached here by analysis of T cell immunodominance. After describing the unpredictability of defining dominant T cell-inducing determinants and the preference of empirical methods, the question of designing a solely T determinant vaccine is explored. In this regard, evidence is presented that T helper cell-inducing and T proliferation-inducing determinants are not necessarily identical. With regard to the influence of other determinants on the molecule, three issues are discussed with relevance to vaccine design: (1) 'preferential partnerships' between T and B cells of certain specificities (2) the existence of suppressor T cells, reactive against non-overlapping determinants (3) competitive antigenic determinants, restricted to the same or to a different MHC molecule.

Animals↗
PubMed1989

How some T cells escape tolerance induction.

A feature common to many animal models of autoimmune disease, for example, experimental allergic encephalomyelitis, experimental autoimmune myasthenia gravis and collagen-induced arthritis, is the presence of self-reactive T cells in healthy animals, which are activated to produce disease by immunization with exogenous antigen. It is unclear why these T cells are not deleted during ontogeny in the thymus and, having escaped tolerance induction, why they are not spontaneously activated by self-antigen. To investigate these questions, we have examined an experimental model in which mice are tolerant to an antigen despite the presence of antigen-reactive T cells. We find that the T cells that escape tolerance induction are specific for minor determinants on the antigen. We propose that these T cells evade tolerance induction because some minor determinants are only available in relatively low amounts after in vivo processing of the whole antigen. For the same reason, these T cells are not normally activated but can be stimulated under special circumstances to circumvent tolerance.

Animals↗