Abbreviations used in this paper. Mls, minor lymphocyte stimulating ; PPD, tuberculin purified de... more Abbreviations used in this paper. Mls, minor lymphocyte stimulating ; PPD, tuberculin purified derivative; SpWMb, sperm whale myoglobin . 83 J . Exp. Med .
Journal of immunology (Baltimore, Md. : 1950), 1979
Quantitative differences in the magnitude of antigen-induced proliferative responses of sensitize... more Quantitative differences in the magnitude of antigen-induced proliferative responses of sensitized lymph node cells between low (C3H/Anf or C3H/Cr) and high (C3H/Hej or CBA/j) responder H-2k mice have been observed 1 to 2 weeks after in vivo sensitization with antigen (OVA, PPD, and GAT). We have shown that antigen presentation is less effective in the sensitized lymph node cell populations from low responder mice compared with those from high responder mice, suggesting that the number and/or functional status of antigen-presenting cells in the regional lymph nodes may be a key factor in determining the magnitude of antigen-induced proliferative responses. These data are consistent with the hypothesis that cell traffic after sensitization plays an important role in determining the immune responsiveness of lymph nodes.
Using a genome-scale approach to study transcription levels in a human CD8+ T-cell clone, a recen... more Using a genome-scale approach to study transcription levels in a human CD8+ T-cell clone, a recent study has suggested that the repertoire of molecules on the surface of T cells is close to being completely characterized.
Page 229. von Herrath MG (ed.): Molecular Pathology of Type 1 Diabetes mellitus. Curr Dir Autoimm... more Page 229. von Herrath MG (ed.): Molecular Pathology of Type 1 Diabetes mellitus. Curr Dir Autoimmun. Basel, Karger, 2001, vol 4, pp 218–238 b Understanding the Interaction of Genetics and Cellular Responses in Nonobese ...
Journal of immunology (Baltimore, Md. : 1950), 2000
Activated T lymphocytes modulate the level of many molecules on their cell surface, including cyt... more Activated T lymphocytes modulate the level of many molecules on their cell surface, including cytokine receptors. This regulation of cytokine receptor expression affects the ability of T cells to respond to cytokines and thus influences the outcome of an immune response. The receptor for IFN-gamma, a proinflammatory cytokine, consists of two copies of a ligand binding chain (IFN-gammaR1) as well as two copies of a second chain (IFN-gammaR2) required for signal transduction. The expression of IFN-gammaR2 is down-regulated at the mRNA level on CD4+ T cells when they differentiate into the Th1, but not the Th2, phenotype. This down-regulation has been demonstrated to depend on the ligand, IFN-gamma, which is produced by Th1 but not Th2 T cells. The regulation of the cell-surface expression of IFN-gamma receptors during primary T cell activation has not been reported. Naive and differentiated T lymphocytes express IFN-gammaR1 at the mRNA level and as a cell-surface protein. In this stud...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1997
Protection against most intracellular pathogens requires T cells that recognize pathogen-derived ... more Protection against most intracellular pathogens requires T cells that recognize pathogen-derived peptides in association with MHC class I molecules on the surface of infected cells. However, because exogenous proteins do not ordinarily enter the cytosol and access the MHC class I-processing pathway, protein-based vaccines that induce class I-restricted CTL responses have proved difficult to design. We have addressed this problem by conjugating proteins, such as OVA, to a short cationic peptide derived from HIV-1 tat (residues 49-57). When APC were exposed in vitro to such protein conjugates, they processed and presented the peptides in association with MHC class I molecules and stimulated CD8+ Ag-specific T cells. Moreover, Ag-specific CTLs were generated in vivo by immunizing mice with histocompatible dendritic cells that had been exposed to protein-tat conjugates.
In these experiments, we studied the role of anti-CD4 (Ox38) monoclonal antibody in the preventio... more In these experiments, we studied the role of anti-CD4 (Ox38) monoclonal antibody in the prevention of heart and/or kidney allograft rejection in low (ACI) and high (Lewis) responder rats. In low responder ACI rats, donor-specific tolerance for heart and kidney allografts (individually or in combination) was achieved by pretransplant anti-CD4 therapy. In high responder Lewis rats, anti-CD4 therapy alone (or combined with anti-CD8 (Ox8), thymectomy or total lymphoid irradiation) did not prevent first-set rejection of heart allografts. This difference was correlated with a more profound and longer lasting CD4+ cell depletion in the low responder strain. Anti-CD4 treatment, however, produced tolerance of kidney transplants in high responder rats. Additionally, anti-CD4 treatment induced tolerance to heart (as well as kidney) allografts in Lewis recipients of combined kidney and heart allografts from ACI. The effects of anti-CD4 treatment thus depend upon the recipient responder status a...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1995
It has been difficult to induce donor-specific transplantation tolerance in high responder Lewis ... more It has been difficult to induce donor-specific transplantation tolerance in high responder Lewis rats. Results presented below demonstrate that amounts of pretransplant anti-CD4 sufficient to allow allograft tolerance in low responder strains (5 mg/kg x 4 days) did not prevent the acute rejection of ACI heart allografts in high responder Lewis recipients. Higher doses of pretransplant anti-CD4 (10 mg/kg, 15 mg/kg, and 20 mg/kg) given alone could delay but not prevent allograft rejection. Pretransplant anti-CD4 combined with anti-CD8, thymectomy, and total lymphoid irradiation all failed to produce tolerance to ACI heart allografts. However, a regimen of anti-CD4 combined with CTLA4Ig allowed indefinite survival of ACI heart allografts (mean survival time, > 100 day). Second-donor matched heart grafts were permanently accepted, and third-party heart grafts were permanently accepted, and third-party heart allografts were rejected by the tolerant recipients. These results suggest a ...
T cells recognize antigenic peptides displayed on the surface of MHC-bearing antigen-presenting c... more T cells recognize antigenic peptides displayed on the surface of MHC-bearing antigen-presenting cells (APCs), and with sufficient costimulation become activated. However, the ability of an APC (even bearing the correct peptide) to initiate and fulfill the requirements for T cell activation is not easily achieved. Naive T cells use multiple copies of a single receptor to survey the vast array of peptides presented on an APC, and require multiple receptor engagements to initiate T cell activation. Dendritic cells (DCs) are specialized cells with optimal capabilities for priming naive CD4+ T cells. Activation occurs, after initial antigen recognition by T cells, followed by a rapid dialogue between the T cells and the DCs. The resulting changes in both the cytoskeleton and the expression or regulation of cell-surface molecules on both cell types act to further strengthen engagement. In this report, we review the fundamentals of CD4+ T helper cell : DC interactions and discuss recent data concerning the molecular characteristics of this engagement.
We examined the incidence of B lymphocyte (HLA-DRw) alloantigens in patients who exhibited elevat... more We examined the incidence of B lymphocyte (HLA-DRw) alloantigens in patients who exhibited elevated antibody titers to native DNA irrespective of their diagnosis. We found a statistically significant (P less than or equal to 0.0001) association between HLA-DRw3 and the presence of antibodies to native DNA not only in patients with a diagnosis of systemic lupus erythematosus but in other patients who did not share that diagnosis. This association supports the existence of a human immune response gene linked to the HLA complex. These data suggest that the hypothesis of an association between HLA and disease operating through disease susceptibility antigens or genes might be invalid and supports an alternative hypothesis, that HLA and disease associations are a manifestation of an immune response gene that controls the production of specific antibodies in any of several disease states.
It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express a... more It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.
We have directed a variety of immunologic studies toward staphylococcal nuclease as a model antig... more We have directed a variety of immunologic studies toward staphylococcal nuclease as a model antigen. Although nuclease is a naturally occurring protein antigen with a complex amino acid composition and globular structure, a pattern of Ir gene control of the humoral response to nuclease comparable to that obtained for simpler copolymers has been observed. The in vitro T-cell proliferative response
GRAIL (gene related to anergy in lymphocytes, also known as RNF128), an ubiquitin-protein ligase ... more GRAIL (gene related to anergy in lymphocytes, also known as RNF128), an ubiquitin-protein ligase (E3), utilizes a unique single transmembrane protein with a split function motif, and is an important gatekeeper of T cell unresponsiveness. While it may play a role in other CD4 T cell functions including activation, survival, and differentiation, GRAIL is most well characterized as a negative regulator of TCR responsiveness and cytokine production. Here, we review the recent literature on this remarkable E3 in the regulation of human and mouse CD4 T cell unresponsiveness.
Abbreviations used in this paper. Mls, minor lymphocyte stimulating ; PPD, tuberculin purified de... more Abbreviations used in this paper. Mls, minor lymphocyte stimulating ; PPD, tuberculin purified derivative; SpWMb, sperm whale myoglobin . 83 J . Exp. Med .
Journal of immunology (Baltimore, Md. : 1950), 1979
Quantitative differences in the magnitude of antigen-induced proliferative responses of sensitize... more Quantitative differences in the magnitude of antigen-induced proliferative responses of sensitized lymph node cells between low (C3H/Anf or C3H/Cr) and high (C3H/Hej or CBA/j) responder H-2k mice have been observed 1 to 2 weeks after in vivo sensitization with antigen (OVA, PPD, and GAT). We have shown that antigen presentation is less effective in the sensitized lymph node cell populations from low responder mice compared with those from high responder mice, suggesting that the number and/or functional status of antigen-presenting cells in the regional lymph nodes may be a key factor in determining the magnitude of antigen-induced proliferative responses. These data are consistent with the hypothesis that cell traffic after sensitization plays an important role in determining the immune responsiveness of lymph nodes.
Using a genome-scale approach to study transcription levels in a human CD8+ T-cell clone, a recen... more Using a genome-scale approach to study transcription levels in a human CD8+ T-cell clone, a recent study has suggested that the repertoire of molecules on the surface of T cells is close to being completely characterized.
Page 229. von Herrath MG (ed.): Molecular Pathology of Type 1 Diabetes mellitus. Curr Dir Autoimm... more Page 229. von Herrath MG (ed.): Molecular Pathology of Type 1 Diabetes mellitus. Curr Dir Autoimmun. Basel, Karger, 2001, vol 4, pp 218–238 b Understanding the Interaction of Genetics and Cellular Responses in Nonobese ...
Journal of immunology (Baltimore, Md. : 1950), 2000
Activated T lymphocytes modulate the level of many molecules on their cell surface, including cyt... more Activated T lymphocytes modulate the level of many molecules on their cell surface, including cytokine receptors. This regulation of cytokine receptor expression affects the ability of T cells to respond to cytokines and thus influences the outcome of an immune response. The receptor for IFN-gamma, a proinflammatory cytokine, consists of two copies of a ligand binding chain (IFN-gammaR1) as well as two copies of a second chain (IFN-gammaR2) required for signal transduction. The expression of IFN-gammaR2 is down-regulated at the mRNA level on CD4+ T cells when they differentiate into the Th1, but not the Th2, phenotype. This down-regulation has been demonstrated to depend on the ligand, IFN-gamma, which is produced by Th1 but not Th2 T cells. The regulation of the cell-surface expression of IFN-gamma receptors during primary T cell activation has not been reported. Naive and differentiated T lymphocytes express IFN-gammaR1 at the mRNA level and as a cell-surface protein. In this stud...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1997
Protection against most intracellular pathogens requires T cells that recognize pathogen-derived ... more Protection against most intracellular pathogens requires T cells that recognize pathogen-derived peptides in association with MHC class I molecules on the surface of infected cells. However, because exogenous proteins do not ordinarily enter the cytosol and access the MHC class I-processing pathway, protein-based vaccines that induce class I-restricted CTL responses have proved difficult to design. We have addressed this problem by conjugating proteins, such as OVA, to a short cationic peptide derived from HIV-1 tat (residues 49-57). When APC were exposed in vitro to such protein conjugates, they processed and presented the peptides in association with MHC class I molecules and stimulated CD8+ Ag-specific T cells. Moreover, Ag-specific CTLs were generated in vivo by immunizing mice with histocompatible dendritic cells that had been exposed to protein-tat conjugates.
In these experiments, we studied the role of anti-CD4 (Ox38) monoclonal antibody in the preventio... more In these experiments, we studied the role of anti-CD4 (Ox38) monoclonal antibody in the prevention of heart and/or kidney allograft rejection in low (ACI) and high (Lewis) responder rats. In low responder ACI rats, donor-specific tolerance for heart and kidney allografts (individually or in combination) was achieved by pretransplant anti-CD4 therapy. In high responder Lewis rats, anti-CD4 therapy alone (or combined with anti-CD8 (Ox8), thymectomy or total lymphoid irradiation) did not prevent first-set rejection of heart allografts. This difference was correlated with a more profound and longer lasting CD4+ cell depletion in the low responder strain. Anti-CD4 treatment, however, produced tolerance of kidney transplants in high responder rats. Additionally, anti-CD4 treatment induced tolerance to heart (as well as kidney) allografts in Lewis recipients of combined kidney and heart allografts from ACI. The effects of anti-CD4 treatment thus depend upon the recipient responder status a...
Journal of immunology (Baltimore, Md. : 1950), Jan 15, 1995
It has been difficult to induce donor-specific transplantation tolerance in high responder Lewis ... more It has been difficult to induce donor-specific transplantation tolerance in high responder Lewis rats. Results presented below demonstrate that amounts of pretransplant anti-CD4 sufficient to allow allograft tolerance in low responder strains (5 mg/kg x 4 days) did not prevent the acute rejection of ACI heart allografts in high responder Lewis recipients. Higher doses of pretransplant anti-CD4 (10 mg/kg, 15 mg/kg, and 20 mg/kg) given alone could delay but not prevent allograft rejection. Pretransplant anti-CD4 combined with anti-CD8, thymectomy, and total lymphoid irradiation all failed to produce tolerance to ACI heart allografts. However, a regimen of anti-CD4 combined with CTLA4Ig allowed indefinite survival of ACI heart allografts (mean survival time, > 100 day). Second-donor matched heart grafts were permanently accepted, and third-party heart grafts were permanently accepted, and third-party heart allografts were rejected by the tolerant recipients. These results suggest a ...
T cells recognize antigenic peptides displayed on the surface of MHC-bearing antigen-presenting c... more T cells recognize antigenic peptides displayed on the surface of MHC-bearing antigen-presenting cells (APCs), and with sufficient costimulation become activated. However, the ability of an APC (even bearing the correct peptide) to initiate and fulfill the requirements for T cell activation is not easily achieved. Naive T cells use multiple copies of a single receptor to survey the vast array of peptides presented on an APC, and require multiple receptor engagements to initiate T cell activation. Dendritic cells (DCs) are specialized cells with optimal capabilities for priming naive CD4+ T cells. Activation occurs, after initial antigen recognition by T cells, followed by a rapid dialogue between the T cells and the DCs. The resulting changes in both the cytoskeleton and the expression or regulation of cell-surface molecules on both cell types act to further strengthen engagement. In this report, we review the fundamentals of CD4+ T helper cell : DC interactions and discuss recent data concerning the molecular characteristics of this engagement.
We examined the incidence of B lymphocyte (HLA-DRw) alloantigens in patients who exhibited elevat... more We examined the incidence of B lymphocyte (HLA-DRw) alloantigens in patients who exhibited elevated antibody titers to native DNA irrespective of their diagnosis. We found a statistically significant (P less than or equal to 0.0001) association between HLA-DRw3 and the presence of antibodies to native DNA not only in patients with a diagnosis of systemic lupus erythematosus but in other patients who did not share that diagnosis. This association supports the existence of a human immune response gene linked to the HLA complex. These data suggest that the hypothesis of an association between HLA and disease operating through disease susceptibility antigens or genes might be invalid and supports an alternative hypothesis, that HLA and disease associations are a manifestation of an immune response gene that controls the production of specific antibodies in any of several disease states.
It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express a... more It has been demonstrated, in certain autoimmune disease models, that pathogenic T cells express antigen receptors of limited diversity. It has been suggested that the T cells responsible for the pathogenesis of type I diabetes mellitus might similarly demonstrate restricted T cell receptor (TCR) usage. Recently, attempts have been made to identify the V beta subset(s) that initiates and/or perpetuates the antiislet response in a mouse model of spontaneous autoimmune diabetes (non-obese diabetic [NOD] mice). In studies reported here, we have bred NOD mice to a mouse strain that congenitally lacks approximately one-half of the conventional TCR V beta alleles. Included in this deletion are TCR V beta gene products previously implicated as being involved in the pathogenesis of NOD disease. By studying second backcross-intercross animals, we were able to demonstrate that this deletion of TCR V beta gene segments did not prevent the development of insulitis or diabetes.
We have directed a variety of immunologic studies toward staphylococcal nuclease as a model antig... more We have directed a variety of immunologic studies toward staphylococcal nuclease as a model antigen. Although nuclease is a naturally occurring protein antigen with a complex amino acid composition and globular structure, a pattern of Ir gene control of the humoral response to nuclease comparable to that obtained for simpler copolymers has been observed. The in vitro T-cell proliferative response
GRAIL (gene related to anergy in lymphocytes, also known as RNF128), an ubiquitin-protein ligase ... more GRAIL (gene related to anergy in lymphocytes, also known as RNF128), an ubiquitin-protein ligase (E3), utilizes a unique single transmembrane protein with a split function motif, and is an important gatekeeper of T cell unresponsiveness. While it may play a role in other CD4 T cell functions including activation, survival, and differentiation, GRAIL is most well characterized as a negative regulator of TCR responsiveness and cytokine production. Here, we review the recent literature on this remarkable E3 in the regulation of human and mouse CD4 T cell unresponsiveness.
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Papers by C. Fathman