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B Benacerraf

Publications and source records attributed to B Benacerraf.

At least 91 records · Page 5Linked to original sources
PubMed1986

T cell-activating protein on murine lymphocytes.

A functional T cell surface molecule, T cell-activating protein (TAP), has been identified on murine lymphocytes. TAP is a protein with an apparent molecular mass of 10-12 kilodaltons (kDa) nonreduced, 16-17 kDa reduced. Cross-linking of TAP can result in profound activation of T lymphocytes to produce lymphokines and to enter the cell cycle. Furthermore, antibody binding to TAP can modulate antigen-driven T cell stimulation. Current data suggest that TAP is physically distinct from the T cell receptor complex. On unstimulated lymphocytes, TAP is expressed on T cells and defines heterogeneity within the major T cell subsets. Its profile of expression is rapidly altered on cell activation. Ontologically, it is first detected in the thymus, where it is found on both the most immature and the most mature cell subsets, and it is functional on both. Together, these TAP+ cells constitute a small fraction of thymocytes. TAP expression, however, defines the immunocompetent compartment of the thymus, and thus could be involved in functional maturation. Finally, the gene controlling TAP expression has been mapped, and is tightly linked to a locus of hematopoietic antigens (Ly-6). TAP is molecularly distinct from these antigens. Furthermore, all of these proteins show a markedly distinct developmental regulation in their cell surface expression.

Animals↗
PubMed1985

T cell development in B cell-deficient mice. II. Serological characterization of suppressor T cell factors (TsF1) produced in normal mice and in mice treated chronically with rabbit anti-mouse IgM antibodies.

Serological analysis of idiotypic specificities present in azobenzenearsonate (ABA)-specific first-order suppressor T cell factors (TsF1) from C.AL-20 and BALB/c mice revealed a significant difference between TsF from these two strains of mice. The idiotypic composition of TsF1 from BALB/c mice appears to be more heterogeneous, and at least two different fractions can be readily identified. One bears the characteristic BALB/c-associated CRI(C) (crossreactive idiotype) determinants, and the other is non-CRI(C)-bearing. Analysis of ABA-specific TsF1 from animals lacking B cells uncovered a fundamental change in the expression of their idiotypic specificities. TsF from rabbit anti-mouse IgM (anti-mu)-treated C.AL-20 mice failed to express the characteristic CRI(A) determinants. Instead, they express CRI(C) specificities. Similarly, TsF1 from anti-mu-treated BALB/c mice did not express their characteristic CRI(C) specificities, but rather express CRI(A) determinants. These experiments provide strong evidence that the Igh restriction specificity of TsF is dictated by the particular idiotypic specificities expressed. They also clearly demonstrate that B cells and their products play an important role in establishing the idiotypic composition and repertoire of suppressor T cells.

Animals↗
PubMed1985

Analysis of antigen presentation by metabolically inactive accessory cells and their isolated membranes.

Several amino acid copolymers are potent immunogens under the control of major histocompatibility complex (MHC)-encoded Ir genes. We have further characterized their accessory-cell-dependent, MHC-restricted presentation to T lymphocytes. We initially characterized their processing requirements by investigating the ability of paraformaldehyde-fixed antigen-presenting cells (APC) to present these copolymers. Fixed APC can present poly(Glu56Lys35Phe9) and poly(Glu60Ala30Tyr10) provided that they have been incubated with antigen prior to fixation. The inability of these same fixed preparations to present soluble antigen indicates a fixation-sensitive antigen-processing step. In contrast, the antigens poly(Glu55Lys35Leu10) and poly(Glu55Lys35Tyr10) can be presented by APC fixed before antigen exposure. This differential requirement for antigen processing was exploited to analyze the events of antigen presentation in two related systems. First, the ability of isolated APC membranes to process and present antigen was assessed. APC membranes can present the antigens poly(GluLysLeu) and poly(GluLysTyr) in a specific and MHC-restricted manner. However, the isolated membranes fail to present either poly(GluLysPhe) or poly(GluAlaTyr), suggesting that such preparations can present but not process antigen. Second, the distinct properties of the various copolymers were used with fixed APC to test the effects of antigen processing on the phenomenon of antigen competition. APC that had processed poly(GluLysPhe) or poly(GluAlaTyr) were subsequently fixed and used to present antigen in the presence or absence of various antagonists. Under these conditions, poly(GluLysLeu) and poly(Glu50Tyr50) could effect specific inhibition, clearly indicating that antigen competition occurs distal to and does not require antigen processing. In contrast, native antigen with an absolute processing requirement is not capable of competing with preprocessed antigen on fixed APC. Taken together, these results suggest that processing is important for the molecular interactions between the copolymer antigens and the APC cell surface that are relevant to both antigen presentation and competitive inhibition.

Antigen-Presenting Cells↗
PubMed1985

Suppressor T-cell factor(s) display an altered pattern of Igh (immunoglobulin heavy chain locus) genetic restriction when developed in an Igh-congeneic host.

Suppressor T-cell factor(s) (TsF1) inhibit the in vivo priming of azobenzenearsonate-specific cytotoxic T-cell responses. The activity of TsF1 is restricted by genes linked to Igh-1 allotypic markers. TsF1 obtained from B6.Igh-1n mice was unable to suppress the immune response in B6.Igh-1b mice and vice versa. However, TsF1 prepared from B6.Igh-1n T cells "parked" in an Igh-congeneic B6.Igh-1b environment displays an additional restriction specificity of the host. Thus, TsF1 prepared from these Igh-chimeric mice suppressed immune responses in both B6.Igh-1n (donor) and B6.Igh-1b (recipient) mice but not in mice of the unrelated strain BALB/c.Igh-1a. The results indicate that the establishment of the suppressor T-cell repertoire is dependent not only upon the genetic background of the individual T cell but also upon the influence of Igh-linked determinants present when T-cell clones are selected during the response.

Animals↗
PubMed1985

I-J as a restriction element in the suppressor T cell system.

This review attempts to sort out the differences between macrophage and T cell I-J determinants. We propose that suppressor T cells have receptors for self-I-J determinants which are expressed on macrophage-like accessory cells. The I-J determinants associated with accessory cells are responsible for the selection of the Ts receptors. Although the major histocompatibility complex is involved in the selection of Ts receptors, the receptors themselves need not be encoded by genes which reside within the MHC. In fact, the molecular genetic evidence presently available has established that suppressor T cell factors do not express gene products associated with the postulated I-J region of the H-2 complex. In spite of the failures of biochemists and molecular geneticists to identify I-J genes and gene products, there is extensive biological data demonstrating the existence of I-J. The activity of anti-I-J reagents has been verified by numerous laboratories. Sera containing anti-I-J activity have been prepared in many strain combinations. Immunization between a variety of strains differing at the purported I-J region produce active anti-I-J antibodies (Murphy et al. 1976, Tada et al. 1976, Pierres et al. 1977, Tada et al. 1978). Furthermore, in many suppressor cell systems the interactions of Ts cells and factors are restricted by I-J (Tada & Okumara 1980, Sorensen & Pierce 1982, Green et al. 1983, Dorf & Benacerraf 1984). Most investigators who have attempted to detect I-J have analyzed T cells. Since we propose that T cells express a complementary anti-I-J receptor, subsequent efforts at identifying I-J should include analysis of macrophage I-J determinants. In spite of extensive biological data, we still do not know if I-J is a protein, carbohydrate or lipid. In addition, the role of H-2 in determining I-J structure is unknown. Nevertheless, the overwhelming biological data demonstrate that I-J is an important structure for suppressor T cell interactions. Much remains to be accomplished, including the characterization of I-J products and locating the I-J genes.

Animals↗
PubMed1985

Reminiscences.

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Allergy and Immunology↗
PubMed1985

T cell development in B cell deficient mice. III. Restriction specificity of suppressor T cell factor(s) produced in mice treated chronically with rabbit anti-mouse mu chain antibody.

A role for Igh linked genes and the idiotypes they encode has been implicated in the activity of a variety of T cell subpopulations. Idiotype restricted T cell function has been observed for helper and suppressor cell populations. The finding that T cell receptor genes are distinct from B cell receptor (Igh) genes strongly argues against a direct role for immunoglobulin genes in the determination of the T cell repertoire. Nevertheless, idiotypic Ig determinants may play an indirect role in influencing the ultimate composition of the T cell repertoire. One approach to this question involves evaluation of T cell activity upon development in an immunoglobulin deficient environment. The availability of antigens which elicit T cell and antibody responses characterized by the expression of dominant crossreactive idiotypes under the control of Igh genes provides an ideal approach to investigate the basis for the expression of Igh-like structures on T cells and the concomitant functional genetic restrictions they determine. Thus, we have prepared B cell deficient mice by continuous treatment, beginning at birth, with rabbit anti-mouse IgM. The network which comprises the suppressor T cell response to azobenzenearsonate (ABA) was then examined in normal and anti-mu treated mice to assess what role, if any, immunoglobulin encoded determinants play in influencing the composition of the peripheral T cell pool. The results clearly demonstrate that the absence of Ig+ B cells leads to major alterations in the composition of the T cell repertoire. Anti-mu treated, but not normal rabbit Ig treated, mice produce TsF1 which fails to suppress cytotoxic T lymphocyte or helper T cell responses of normal syngeneic mice, yet efficiently suppresses those of syngeneic anti-mu treated recipients. Reciprocally, normal TsF1, though suppressive in normal Igh-1 syngeneic recipients, fails to affect the development of responses in anti-mu treated syngeneic mice. TsF1 obtained from anti-mu treated mice is antigen-specific. Testing of anti-mu TsF in a variety of normal or anti-mu treated recipients reveals no MHC restrictions. In marked contrast, anti-mu TsF reflects a novel pattern of Igh functional restrictions. The observed Igh restrictions were found to map to the idiotype encoding VH regions of the Ig heavy chain gene cluster (Igh-VH). The results demonstrate that T cell maturation in the virtual absence of environmental immunoglobulin can lead to profound changes in the composition of the T cell compartment. The means by which the absence of Ig encoded determinants leads to such changes is speculated upon.

Agammaglobulinemia↗
PubMed1984

Inhibition of antigen-specific T lymphocyte activation by structurally related Ir gene-controlled polymers. II. Competitive inhibition of I-E-restricted, antigen-specific T cell responses.

Our previous studies have defined a highly specific competitive inhibition between a pair of structurally related antigens (GT and GAT) for antigen presentation by accessory cells. The present report investigates this phenomenon in a second antigenic system, which is controlled by a distinct Ir gene product. Two GL phi-specific, I-Ed-restricted, interleukin 2-producing T cell hybridomas were constructed. The antigenic fine specificity of these two hybrid clones was distinct. One hybrid reacted solely with GL phi while the second cross-reacted with GLleu and GLT. These latter two copolymers, as well as the antigen GL, were found to inhibit the GL phi response of the non-cross-reactive hybrid. The structurally related antigen G phi was not inhibitory for this clone's response. The cross-reactive GL phi hybrid could also be inhibited, but, in this case, G phi and not GL caused the inhibition. Reciprocal inhibitions could be demonstrated between these and other hybrids (e.g., GAT responsive), indicating a very high degree of specificity to the inhibition. The inhibition caused by the various copolymers was reversible by increasing the concentration of GL phi, This effect was localized to the antigen-presenting cell and not the T cell hybridoma. Functionally, this competition did not appear to be for antigen uptake or general antigen processing. These findings generalize the phenomenon of antigen competition to a second antigen system in the context of a second Ia molecule. The possible mechanisms accounting for the complex pattern of specificities in this system are discussed.

Alleles↗
PubMed1984

Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors.

The present study examines the ability of hapten-specific murine splenic B lymphocytes to present hapten-proteins to carrier-specific T cell hybridomas. BALB/cB cells specific for 2,4,6-trinitrophenyl (TNP) were isolated from spleens of immune mice by elution from TNP-gelatin-coated dishes. Such cells presented the TNP-modified terpolymer, GL phi, at concentrations as low as 0.1 microgram/ml, to a GL phi-specific, I-Ed-restricted, interleukin 2-producing T cell hybridoma. In contrast, the same B lymphocytes required 1,000-fold higher concentrations of unmodified GL phi to stimulate the same T cell hybridoma. The presentation of low concentrations of TNP-GL phi by TNP-specific B lymphocytes was significantly or completely blocked by anti-Ig antibody or TNP-proteins, indicating that surface Ig receptors were critically involved in this phenomenon. Finally, binding of TNP-proteins did not alter the ability of the B cells to present unrelated, unhaptenated proteins or to stimulate alloreactive T cells. These results suggest that surface Ig receptors serve to focus antigens onto specific B lymphocytes and that such cells are highly efficient at presenting linked antigenic determinants to T cells. The implications of these findings for the mechanisms of physiologic, histocompatibility-restricted T-B collaboration are discussed.

Animals↗
PubMed1984

Analysis of thymocyte MHC specificity with thymocyte hybridomas.

Medullary, peanut agglutinin-negative (PNA-), thymocytes were activated in vitro with either exogenous interleukin 1 (IL-1) or accessory cells. T cell blasts from these cultures were subsequently fused to BW5147 to generate thymocyte hybridomas. Fusion frequencies similar to those obtained with peripheral T lymphocytes were observed. A high frequency of these hybrids are triggered to produce IL-2 in the presence of syngeneic accessory cells. Exogenous, nominal antigens do not appear to be required for this activation. Using accessory cells from a series of recombinant inbred mice, the specificity of this hybrid-accessory cell interaction could be mapped to either I-Ak or I-Ek or both. This was confirmed by blocking with alpha Ia monoclonal antibodies (mAbs). A high frequency of these self-reactive cells are also alloreactive. Interestingly, several clones were identified that appear to recognize public Ia determinants broadly shared by different alleles and genetic subregions. Such specificities appear to contrast with those of peripheral T lymphocytes whose specificity is dominated by the genetically polymorphic portion of the Ia molecule. These results document the clonal specificity occurring in the cultures of in vitro activated thymocytes and allow an analysis of at least a portion of the intrathymic repertoire for major histocompatibility complex (MHC) determinants. The implications of these findings are discussed.

Animals↗
PubMed1984

Selective modification of a private I-A allo-stimulating determinant(s) upon association of antigen with an antigen-presenting cell.

A large panel of alloreactive, interleukin 2 (IL-2)-producing T cell hybridomas was constructed from B10 alpha BALB/c primary mixed lymphocyte cultures (MLC). Functional hybrids had specificity for either I-Ad or I-Ed. These cells were used to probe determinants on Ia molecules in an attempt to detect molecular association between a nominal antigen and an Ia molecule on an antigen-presenting cell (APC). The response of a small number of these clones was significantly blocked by the addition of the Ir gene-controlled copolymer L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT) to culture. A comparison of the inhibited and uninhibited hybrids revealed an identical dose response curve. Further, both types of hybrids were activated by the same stimulator cell and frequently recognized the identical Ia molecule on that cell. Nevertheless, the inhibitory effect of GAT was localized to the stimulator cell and not to the T cell hybrids. All of the hybrids whose stimulation was blocked had specificity for the I-A molecule, which is the gene product known to control and restrict responsiveness to GAT. Further, only GT, but not a number of other related antigens, was also specifically inhibitory, which correlates with the known associational specificity of these antigens on an APC. Finally, the same stimulator cell could be shown to coordinately lose an allostimulatory determinant(s), while it was gaining an I-Ad plus GAT determinant(s). The implications of these findings on the nature of antigen-Ia association and on the role of polymorphic Ia determinants are discussed.

Animals↗
PubMed1984

Monoclonal antibodies to tissue-specific cell surface antigens. I. Characterization of an antibody to a prostate tissue antigen.

Monoclonal antibodies were raised to PC-3 human prostate adenocarcinoma cells, and one hybridoma, designated F77-129, was extensively purified and used to characterize a PC-3 antigen. The F77-129 antibody also showed serological reactivity with the Du-145 prostate cancer line and with three of four breast carcinoma lines tested; it showed variable binding to a colon carcinoma line. Several other lines tested, including melanomas, fibrosarcomas, and leukemias, were completely negative. Immunoperoxidase staining of frozen surgical specimens showed binding to both normal and malignant prostate and breast tissue. Injection of radioiodinated F77-129 into tumor-bearing nude mice showed specific in vivo targeting to prostatic cancer implants. The antigen also showed surface modulation by bound antibody, suggesting possible clinical utility of this antibody in delivering immunotoxins to tumors.

Adenocarcinoma↗