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PubMed2004

The somatic generation of immune recognition. 1971.

Antibody specificity is determined by structural v-genes that code for the amino acid sequences of the variable regions of antibody polypeptide chains. The present hypothesis proposes that the germ-cells of an animal carry a set of v-genes determining the combining sites of antibodies directed against a complete set of certain class of histocompatibility antigens of the species to which this animal belongs. The evolutionary development of this set of v-genes in phylogeny is traced back to the requirements for cell to cell recognition in all metazoa. The hypothesis leads to a distinction between two populations of antigen-sensitive cells. One population consists of cells forming antibodies against foreign antigens; these lymphocytes have arisen as mutants in clones descending from lymphocytic stem cells which expressed v-genes belonging to the subset (subset S) coding for antibody against histocompatibility antigens that the individual happens to possess. The other population consists of allograft rejecting lymphocytes that express v-genes of the remaining subset (subset A) coding for antibody against histocompatibility antigens of the species that the individual does not possess. The primary lymphoid organs are viewed as mutant-breeding organs. In these organs (e.g. in the thymus), the proliferation of lymphocytes expressing the v-genes of subset S and the subsequent suppression of the cells of these "forbidden" clones, leads to the selection of mutants cells expressing v-genes that have been modified by spontaneous random somatic mutation. This process generates self-tolerance as well as a diverse population of antigen-sensitive cells that reflects antibody diversity. The proliferation in the primary lymphoid organs of lymphocytes expressing v-genes of subset A generates the antigen-sensitive cell population that is responsible for allo-aggression. The theory explains how a functional immune system can develop through a selection pressure exerted by self-antigens, starting during a period in early ontogeny that precedes clonal selection by foreign antigens. The hypothesis provides explanations for the variability of the N-terminal regions of antibody polypeptide chains, for the dominant genetic control of specific immune responsiveness by histocompatibility alleles, for the relative preponderance of antigen-sensitive cells directed against allogeneic histocompatibility antigens, for antibody-idiotypes, for allelic exclusion, for the precommitment of any given antigen-sensitive lymphocyte to form antibodies of only one molecular species and for the cellular dynamics in the primary lymphoid tissues.

Animals↗
PubMed2006

Mechanisms of CTLA-4-Ig in tolerance induction.

The size of the peripheral T lymphocyte pool remains relatively constant throughout adult life, but individual populations undergo expansion and contraction upon antigen encounter due to signals delivered by members of the B7-CD28 family of costimulatory molecules. This family includes receptors on T cells that can provide either activating or inhibitory signals. In general, activation occurs in response to pathogens, when lymphocyte expansion and acquisition of effector functions is appropriate. Conversely inhibitory receptors provide down-modulating signals that help terminate immune responses and maintain self-tolerance. The activating receptor CD28 engages the same B7-1 and B7-2 molecules as the inhibitory receptor cytotoxic T lymphocyte antigen 4 (CTLA-4), although with reduced affinity than CTLA-4. In addition to this direct competitive mechanism, CTLA-4 can directly inhibit T cell receptor (TCR) signals independently of CD28 expression and recent findings indicate that CTLA-4 may also operate through reverse signaling on ligand-expressing cells. Fusion proteins between the extracellular domain of CTLA-4 and an immunoglobulin Fc portion have been created that have potent immunosuppressive properties in animal models of transplantation and autoimmunity and that show great promise in clinical trials. Like CTLA-4, CTLA-Ig, is thought to selectively prevent activation of CD28 by interacting with B7-1 and B7-2. In addition, CTLA-4-Ig can bind to B7 molecules expressed on dendritic cells and activate a pathway of tryptophan catabolism that can lead to indirect inhibition of lymphocyte activation and T cell death. In this review, we will focus on the current knowledge of the mechanisms of action of CTLA-4 and CTLA-4-Ig.

Abatacept↗
PubMed2002

CpG-ODN-induced inflammation is sufficient to cause T-cell-mediated autoaggression against hepatocytes.

Autoimmune diseases are often associated with microbial infections. Molecular mimicry between microbial antigens and self-epitopes has been suggested as a mechanism for breaking self-tolerance and induction of autoimmunity. Since infections also cause inflammatory responses we explored the role of local inflammation in organ-specific autoimmunity. For this purpose, transgenic mice were used expressing the MHC class I molecule Kb exclusively on hepatocytes. These mice exhibit Kb-specific tolerance as exemplified by the acceptance of Kb+ grafts. Inflammatory reactions were induced by injection of immunostimulatory cytosine-phosphorothioate-guanine (CpG)-rich oligodeoxynucleotides (ODN). Application of CpG-ODN is sufficient to break tolerance in vivo, and to cause activation of Kb-specific CD8+ T cells and subsequent autoaggression against hepatocytes. The CpG-ODN-induced inflammation appears to have two major effects. First, it causes infiltration of T cells into the liver parenchyma. Second, adhesion and costimulatory molecules are up-regulated on hepatocytes so that the infiltrating CD8+ T cells encounter Kb on hepatocytes, which display an APC-like phenotype, resulting in activation and tissue damage. Autoimmune hepatitis can be maintained for at least eight weeks by repeated application of CpG-ODN but subsides after termination of the inflammatory stimulus, suggesting the requirement of additional factors for a self-perpetuation of autoimmunity. These observations describe an additional pathway for the induction of autoimmunity, i.e. in the absence of microbial antigens inflammatory reactions alone can lead to infiltration of T cells into organs, resulting in breaking of tolerance and autoaggression. Moreover, the results provide evidence that T cell activation can take place not only in draining lymph nodes but also directly on parenchymal cells.

Animals↗
PubMed2006

ERK signaling is a molecular switch integrating opposing inputs from B cell receptor and T cell cytokines to control TLR4-driven plasma cell differentiation.

Differentiation of B cells into plasma cells represents a critical immunoregulatory checkpoint where neutralizing Abs against infectious agents must be selected whereas self-reactive Abs are suppressed. Bacterial LPS is a uniquely potent bacterial immunogen that can bypass self-tolerance within the T cell repertoire. We show here that during LPS-induced plasma cell differentiation, the ERK intracellular signaling pathway serves as a pivotal switch integrating opposing inputs from Ag via BCR and from the two best characterized B cell differentiation factors made by T cells, IL-2 and IL-5. Continuous Ag receptor signaling through the RAS/MEK/ERK pathway, as occurs in self-reactive B cells, inhibits LPS induction of Blimp-1 and the plasma cell differentiation program. Differentiation resumes after a transient pulse of Ag-ERK signaling, or upon inactivation of ERK by IL-2 and IL-5 through induction of dual-specificity phosphatase 5 (Dusp5). The architecture of this molecular switch provides a framework for understanding the specificity of antibacterial Ab responses and resistance to bacterially induced autoimmune diseases such as Guillain-Barré syndrome.

Animals↗
PubMed1992

Induction of tolerance to an IgG autoantibody.

Nonautoimmune mice transgenic for the heavy chain of an IgG2b anti-double-stranded-DNA antibody express the transgene in lymphoid organs and display partial allelic exclusion of this gamma 2b transgene. The spleens of these mice are characterized by marked B-cell depletion. Although there are B cells in these mice that express the transgene and recognize double-stranded DNA, they are anergic in vivo. Recovery from the state of anergy occurs in vitro after lipopolysaccharide stimulation. Thus this transgenic model demonstrates the induction of self tolerance to an IgG autoantibody.

Animals↗
PubMed1991

Tolerance and suppressor mechanisms in experimental autoimmune encephalomyelitis: implications for immunotherapy of human autoimmune diseases.

Recent advances in understanding antigen recognition at the level of the trimolecular complex have provided new approaches for selective immunotherapy. Many of these approaches have been applied successfully to the animal model experimental autoimmune encephalomyelitis, and some are being tested in the human disease multiple sclerosis. In addition, new approaches utilizing nonspecific modulation of immune function are being explored in animals and humans. Immunospecific therapy in autoimmune diseases will ultimately be based on understanding how the normal immune system maintains unresponsiveness to self and how this state of self-tolerance is broken. Strategies for specific immune intervention in human diseases based on components of the trimolecular complex will have to take into account the polymorphism of the major histocompatibility complex in humans and the degree of heterogeneity among autoimmune T cells that react with an autoantigen.

Adjuvants, Immunologic↗
PubMed1994

Ionizing radiation and autoimmunity. Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells.

Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and the peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4+ T cells mediated the autoimmune prevention but CD8+ T cells did not. CD4+ T cells also appeared to mediate the TLI-induced autoimmune disease because CD4+ T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells.

Animals↗
PubMed1994

Mechanisms of transplantation tolerance.

Transplantation tolerance, the long-term acceptance of grafted tissue in the absence of continuous immunosuppression, remains an elusive goal in humans, but it has been achieved in animal models using numerous approaches. The mechanisms behind graft acceptance vary according to the means used to create the state of acceptance. Several major mechanisms can now be recognized. While thymic deletion of T cells appears to be a mainstay of self-tolerance, its role in transplantation tolerance now seems to be less significant. In contrast, extrathymic mechanisms of transplantation tolerance seem to be major factors in long-term graft acceptance. If donor antigens are presented in a nonimmunogenic manner on the graft, e.g. due to modification of graft tissue by culture, peripheral T cells of the recipient may ignore the graft. Alternatively, nonstimulatory presentation of donor antigens on graft tissue can induce a state of unresponsiveness in recipient T cells, i.e. anergy, rather than activating them to destroy the graft. Suppression mechanisms also operate to control graft rejection and may be specific or nonspecific in nature. Specific suppression mechanisms might act in an idiotype or antigen-specific fashion, and evidence is accumulating that this may be mediated through the elaboration of cytokines. Donor antigen-specific T cells may be activated to produce "protective" cytokines which then regulate the generation of destructive T cells. Future therapies will be aimed at affecting graft acceptance through these peripheral mechanisms.

Animals↗
PubMed1998

Human extracellular proteins display a different pattern of local sequence similarity with the four classes of human T-cell receptor V-regions than foreign proteins and human intracellular proteins: a preliminary report.

A pool of 110 randomly selected/generated amino acids sequences was used to perform specific local sequence similarity alignment analysis with the pool of 279 reported sequences of human T-cell receptor (TCR) V-regions. The 110 analyzed sequences were divided, according to their origin and nature, into six protein groups, as: human intracellular (hi), extracellular/transmembrane (he) and extracellular adhesive matrix (ha) proteins, 'average' human proteins (hum), proteins of non-human origin (nhum) and randomly generated quasi-protein sequences (r). These sequences were decomposed into all their overlapping 11-mer segments, generating a total of 56,836 derived peptides (at least 8000 per group). Each derived peptide was aligned with the 279 human TCR V-regions and assigned to the category (alpha-like, beta-like, gamma-like or delta-like) corresponding to the class (V alpha, Vbeta, Vgamma or Vdelta) of the V-region encompassing the most similar segment, as determined by the performed similarity-search. The six protein groups were found to differ significantly in their distribution of derived peptides among the four categories. According to the binomial tests results, human proteins from the extracellular compartment (he, ha) comprise a higher proportion of delta-like segments (P = 2.3 x 10(-2) and P < 10(-8), respectively) than the 'average' human proteins (hum). In addition, and in accordance with this finding, proteins that are normally not found in that topological compartment comprise a lower proportion of delta-like peptides (P = 1.4 x 10(-5) and P < 10(-8) for groups nhum and hi, respectively) than the 'average' human proteins (hum). In contrast, these proteins comprise a higher proportion of gamma-like segments (P = 8.3 x 10(-3), P = 1.4 x 10(-3) and P = 1.7 x 10(-4), for groups r, nhum and hi, respectively) than the 'average' human proteins (hum). These findings indicate significant differences between proteins encountered in the extracellular compartment--that are normally immunologically tolerated--and those the presence of which is usually non-tolerated. The results suggest that the discrimination and the reaction of the human immune network to proteins found in the extracellular compartment correlate with the proteins' pattern of preferential local sequence similarity with the Vgamma and Vdelta classes of human TCR V-regions, implying a specific and an important role of gammadelta-cells in the maintenance of the immune homeostasis. Whether this implication represents a rule associated with self-tolerance, will be investigated by future analyses.

Amino Acid Sequence↗
PubMed1995

Aod1, the immunoregulatory locus controlling abrogation of tolerance in neonatal thymectomy-induced autoimmune ovarian dysgenesis, maps to mouse chromosome 16.

Mice thymectomized at three days of age (D3Tx) develop during adulthood a variety of organ-specific autoimmune diseases, including autoimmune ovarian dysgenesis (AOD). The phenotypic spectrum of AOD is characterized by the development of anti-ovarian autoantibodies, oophoritis, and atrophy. The D3Tx model of AOD is unique in that disease induction depends exclusively on perturbation of the normal developing immune system, is T-cell-mediated, and is strain specific. For example, D3Tx A/J mice are highly susceptible to AOD, whereas C57BL/6J mice are resistant. After D3Tx, self ovarian antigens, expressed at physiological levels, trigger an autoimmune response capable of eliciting disease. The D3Tx model provides, therefore, the opportunity to focus on the mechanisms of self-tolerance that are relevant to disease pathogenesis. Previous studies indicate that the principal mechanisms involved in AOD susceptibility are genetically controlled and govern developmental processes associated with the induction and maintenance of peripheral tolerance. We report here the mapping of the Aod1 locus to mouse chromosome 16 within a region encoding several loci of immunologic relevance, including scid, Igl1, VpreB, Igll, Igl1r, Mtv6 (Mls-3), Ly-7, Ifnar, and Ifgt.

Animals↗
PubMed1997

Is CTLA-4 a master switch for peripheral T cell tolerance?

The CD28/CTLA-4 and B7 families of cell surface molecules regulate a complex pathway of T cell signals that profoundly affect peripheral T cell responses. On the one hand, CD28/B7-mediated T cell costimulation is essential for the development and maintenance of T cell responses. In contrast, the prevailing data suggest that the engagement of CTLA-4 with the same B7 ligands down-regulates the initiation and progression of immune responses. This commentary examines the role of CTLA-4-mediated signaling in the regulation of the immune response, leading to the hypothesis that the CTLA-4/B7 interaction plays an essential role in the establishment of peripheral self-tolerance as well as the regulation of normal T cell immunity.

Abatacept↗
PubMed2000

Autologous graft-versus-host disease after CD34+-purified autologous peripheral blood progenitor cell transplantation.

Autologous graft-versus-host disease (GVHD) has been frequently reported after cyclosporine A (CsA) administration in the autologous setting. This complication is related to the disruption of self-tolerance mechanisms induced by CsA and may exert an antitumor effect. We report the spontaneous occurrence of autologous GVHD after CD34+-purified peripheral blood progenitor cell transplantation (PBPCT) in 5 out of 24 consecutive patients (20.8%). The syndrome was characterized by skin rash (5/5), pruritus (5/5), eosinophilia (5/5), and fever (2/5) occurring at a median of 37 days (range 22-60) after transplantation. Diagnosis was confirmed by skin biopsy in all patients. The syndrome was self-limiting, lasted a median of 25 days, and did not require treatment. The rate of autologous GVHD was high after CD34+-purified autologous PBPCT. In fact, no autologous GVHD was documented in an historical control of 100 consecutive patients submitted to unmanipulated PBPCT at the same institution. The manipulation of the graft by the purging procedure causes a profound T lymphocyte depletion, thus possibly perturbing the equilibrium between autoregulatory cells and autocytotoxic T cells. These observations add new interest to the antitumor efficacy of autologous GVHD and suggest new questions regarding the role of transplantation for autoimmune diseases.

Adolescent↗
PubMed1991

Evidence against suppressor cell involvement in naturally acquired tolerance of a minor histocompatibility antigen.

The hypothesis was investigated that suppressor cells may be responsible for maintenance of immunologic tolerance of a minor H3 antigen in mice that express the antigen naturally. Lymphoid cell populations from B6.C-H-24c (HW54) mice, a congenic-resistant strain histoincompatible with H-24b-expressing C57BL/6 (B6) mice only with respect to the H-24 locus, were examined in cell-transfer experiments to see if they contained naturally arising H-24c-specific suppressor cells. The H-24 antigen was chosen for these studies because, unlike most other minor and major histocompatibility (H) antigens, it is not detectable on mature lymphoid cells by any of several functional criteria. Thus transfer of HW54 lymphoid cells to B6 hosts could be done without the complication of inducing hyporesponsiveness de novo in the host, as occurs with other minor H antigens that are expressed on lymphocytes. B6 hosts were given HW54 skin grafts along with HW54 lymphoid cells to assess their tolerance of the H-24c-encoded antigen. The hosts were either (1) normal, nonimmune B6 mice; (2) B6 mice rendered immunodeficient by thymectomy and irradiation (TXB) and repopulated with H-24c-immune B6 lymphocytes; or (3) TXB B6 hosts repopulated with nonimmune B6 lymphocytes. In each case it was found that the additionally infused HW54 lymphoid cells did not suppress the ability of these hosts to reject HW54 skin grafts. In other words, HW54 lymphoid cells appear not to possess suppressive activity specific for the H-24c antigen that might maintain antigen-specific natural tolerance. Additional experiments were performed to determine whether HW54 lymphoid cells can inhibit the ability of sublethally irradiated B6 mice to regain the capacity to reject HW54 skin. The purpose of these experiments was to determine whether there are naturally occurring HW54 lymphoid cells that can suppress the development of lymphocytes potentially reactive to H-24c antigen that presumably emerge in B6 mice following sublethal irradiation. Such suppressor cells would be candidate initiators of self-tolerance. Here, too, no evidence for such suppressor cells was obtained.

Animals↗
PubMed1993

[Recent advances in physiopathology of autoimmune diseases and their therapeutic implications].

Auto-immune diseases (AID) represent an heterogeneous group of chronic inflammatory diseases which do not seem to result from the direct pathogenic effect of microorganisms or xenobiotics. Some AID are associated with the production of autoantibodies which, in some patients, may be involved in the development of tissue damages. In other AID, as in most experimental models of AID, T cells are responsible for the generation of tissue lesions by their cytotoxic activity or by the synthesis of cytokines. Mechanisms by which T and B cells are educated to tolerate self antigens are numerous and operate both in central lymphoid organs (thymus, fetal liver, bone marrow) and at the periphery. They imply either the destruction of autoreactive lymphocytes (clonal deletion) or their inactivation (clonal anergy). Recent advances in analyzing the mechanisms of autoimmunity have opened new therapeutical possibilities which are evaluated in spontaneous and experimental animal models of AID. Among the most promising approaches are the intervention on the cytokine network, T cell and peptide vaccination, oral tolerance and non depleting monoclonal antibodies.

Autoimmune Diseases↗
PubMed1993

Induction of anti-hepatitis B surface antigen (HBsAg) antibodies in HBsAg producing transgenic mice: a possible way of circumventing "nonresponse" to HBsAg.

As a model for studying possible mechanisms of nonresponse toward hepatitis B surface antigen (HBsAg) in hepatitis B virus (HBV) carriers, we used transgenic (Tg) mice which constitutively express this antigen in the liver from before birth. The mice secrete large amounts of HBsAg particles into the sera without producing antibodies. Tg and control mice were immunized with either recombinant HBsAg particles of a different subtype, or with recombinant hybrid HBsAg particles carrying a human immunodeficiency virus (HIV) envelope determinant. The presence of determinants to which the mice are tolerant on the injected particles does not hamper the response to the foreign epitope. Moreover, a weak but significant anti-HBs response is clearly detectable in Tg mice immunized with these particles. Antibodies to epitopes carried by the transgenic antigen are made even after injection of homologous antigen, and a concomitant decrease in circulating HBsAg is observed. This immune response does not induce any liver damage. It was demonstrated that in these Tg mice, B cell self-tolerance toward HBsAg can be overcome by immunization. This phenomenon raises the possibility of designing more effective methods of immunotherapy for HBV carriers.

Animals↗
PubMed2005

Regulatory T cells and tumor immunity.

Central deletion of "self-reactive" T cells has been the textbook paradigm for inducing "self-tolerance" in the periphery and the concept of a role of T cell-mediated suppression in this process has long been controversial. A decisive shift in the opinion on suppressor T cells has lately occurred with the observations of Sakaguchi's group that linked a class of CD4+CD25+ T cells to the prevention of autoimmunity from neonatal thymectomy in mice. These CD4+CD25+ T cells have been named T regulatory (Treg) cells. They are believed to be selected in the thymus as an anti-self repertoire. Hence they were referred to as natural T regulatory (nTreg) cells. Presently, in addition to their role in autoimmunity, they are believed to exert regulatory function in infection, in transplantation immunity as well as in tumor immunity. In contrast to these nTreg cells, another class of CD4+ Treg cells also exercises regulatory function in the periphery. These Treg cells are also CD4+ T cells and after activation they also become phenotypically CD4+CD25+. They are, however induced in the periphery as Treg cells. Hence, they are termed as induced Treg (iTreg) cells. There are major differences in the biology of these two types of Treg cells. They differ in their requirements for activation and in their mode of action. Nonetheless, evidence indicates that both nTreg cells and iTreg cells are involved in the control of tumor immunity. The question of how to circumvent their regulatory constraints, therefore, has become a major challenge for tumor immunologists.

Humans↗
PubMed2005

The role of CD4+CD25+ regulatory T cells in viral infections.

Many virus infections result in the suppression of one or more functions of the immune system. Multiple mechanisms have been proposed to explain viral-induced immunosuppression, including an imbalance in the cellular Th1/Th2 or cytokine profile, induction of anergy, depletion of effector cells and most recently the activation of CD4+CD25+ regulatory T (T reg) cells. CD4+CD25+ T reg cells are a subset of circulating CD4+ T cells with suppressive properties. CD4+CD25+ T reg cells were first identified in mice as cells capable of maintaining self-tolerance by suppressing autoreactive T cells. This review focuses on interactions between CD4+CD25+ T reg cells and viral pathogens. Most cases in which CD4+CD25+ T reg cells participate in response to infection reported so far involve chronic or persistent viral infections. Examples have been growing recently and include members of different viral families including retroviridae, herpesviridae and picornaviridae. It is currently not known how microbes are recognized by CD4+CD25+ T reg cells and whether exoantigen-specific T reg cells are of the same lineage as self-reacting natural T reg cells or represent peripherally induced counterparts derived from CD4+CD25- T cells. The findings that T reg cells influence the functional immunity during viral infections, however, might indicate that, in some cases, virus-specific T reg cells not only influence immune pathology or prevent pathogen elimination but also can promote a generalized state of immunosuppression in vivo such that the host is more susceptible to secondary infections with other pathogens or has reduced resistance to tumors. Conceivably, the activities of T reg cells might be one of the contributing reasons why it has been difficult so far to produce effective vaccines against some persisting viral infections.

Animals↗
PubMed2000

Autoantigen-responsive T cell clones demonstrate unfocused TCR cross-reactivity toward multiple related ligands: implications for autoimmunity.

It has been suggested that the cross-reaction of a single T cell receptor with multiple different peptide ligands is a mechanism for maintaining a diverse yet compact immune repertoire. In the context of autoimmune disease it is important to understand how this property is balanced against the maintenance of self-tolerance. Specifically, whether the cross-reactivity inherent in the immune system is focused or unfocused will have important consequences for the development of autoimmune disease. If cross-reactivity is "focused," then in an immune response to a foreign antigen all T cell receptors that recognize the foreign antigen will cross-react with a specific autoantigenic peptide. However, if cross-reactivity is "unfocused," an immune response to a foreign antigen will result in the activation of a small number of self-reactive cells within a larger pool of cells specific for the foreign antigen. We have tested whether cross-reactivity is focused or unfocused by generating a panel of T cell clones that respond to two closely related ligands. W144 is an autoantigenic peptide of myelin proteolipid protein, PLP 139-151 (HSLGKWLGHPDKF), and Q144 is an altered peptide of PLP 139-151 bearing a glutamine for tryptophan substitution at position 144. The Q144-responsive clones have a broad degree of cross-reactivity with other position 144 substituted peptides. We find that despite their characteristic responses to Q144 and W144, the patterns of responses of these clones to other structurally related ligands are random, demonstrating that cross-reactivity is unfocused in the absence of selection. Maintaining a diverse range of cross-reactive interactions may limit nonspecific responses to autoantigens.

Amino Acid Sequence↗