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D H Sherr

Publications and source records attributed to D H Sherr.

At least 55 records · Page 3Linked to original sources
PubMed1986

Regulation of hapten-specific T and B cell responses by suppressor cells.

We have described a model system of immunoregulation in which gene products associated with both the H-2 and Igh complexes guide a series of cellular interactions. The Igh restriction represents the requirement for T cell recognition of Igh-linked NPb-related idiotypic determinants. The data provide additional evidence that the T and B cell Igh products are distinct. Immunoglobulin products are involved in the selection of T cell receptors; Igh genes are not expressed in T suppressor cell. The H-2 restrictions generally involve the I-J subregion. These restrictions are imposed by the presentation of antigen or suppressor factor on a specialized population of I-J bearing, antigen-presenting cells, thereby functioning in a manner analogous to that proposed for the induction of helper T cells. The NP suppressor cell pathway consists of multiple cellular elements, including at least 3 distinct T cell populations and 2 or more distinct antigen-presenting populations. Generally, specific soluble suppressor factors produced by each Ts cell subset are involved in the cellular communication process. The terminal phases of the suppressor cell cascade involve an antigen dependent non-specific bystander mechanism. Tables IX and X summarize our present view of the NP suppressor cell cascade. It is still not possible to include all the other experimental models involving suppressor cell interactions into the above scheme. However, the disparities between the various systems have in some cases narrowed and in other instances suggested that multiple mechanisms of immune regulation may occur concurrently.

Animals↗
PubMed1985

Mechanism controlling the genetic restrictions of an NP-specific suppressor factor that inhibits B cell responses.

The mechanism of B cell suppression by a T cell hybridoma-derived monoclonal effector suppressor factor (TsF3) was studied in the 4-hydroxy-3-nitrophenyl acetyl (NP) system. The NP-specific effector suppressor cells that produce TsF3 are Lyt-1-, 2+, I-J+, NP-binding T cells and are induced by immunization with NP conjugates. Monoclonal TsF3 inhibits both T cell activity as measured by suppression of contact sensitivity responses and B cell function as measured by suppression of antibody production to both T-independent and T-dependent antigens. The present studies were designed to specifically investigate the mechanisms and genetic restrictions that govern the interactions between TsF3 and its target cells in the plaque-forming cell (PFC) response. The results show that the target of TsF3 is a splenic adherent cell. Suppression will occur only if the restriction specificity of the TsF3 matches the H-2 genotype of the adherent population. Once this TsF3-adherent cell interaction has occurred, suppression of NP-specific B cells can occur across an H-2 barrier. The data also demonstrate that Igh-linked gene products do not appear to play a part in the TsF3-mediated suppression of in vitro PFC responses, which contrasts with the requirements for regulation of T cell-mediated contact sensitivity responses.

Animals↗
PubMed1985

An in vitro system for the generation of suppressor cells and the requirement for B cells in their induction.

An in vitro method for the generation of effector suppressor cells (Ts3) was developed. By utilizing this protocol, it was possible to investigate both the cellular and genetic requirements for suppressor cell induction. It was determined that populations containing Ts3 cells can be induced after a 4-day culture of spleen cells and antigen. These Ts3 cells are similar to Ts3 cells generated by in vivo immunization. Both populations are I-J+, bind NP hapten, bind NP hapten, bear receptors which share NPb idiotypic determinants with anti-NP antibodies, function during the effector phase of the immune response, and require activation with Ts2 cells. Generation of Ts3-containing populations required both nylon wool-nonadherent T cells and a nylon-adherent, B cell-enriched population from an Igh-identical donor. T cells cultured with antigen alone or with syngeneic macrophages and antigen did not develop suppressive activity. Lytic treatment of the nylon-adherent population with a B cell-specific monoclonal antibody (J11d) removed the ability to generate suppressor cells. These results imply that the induction of suppressor T cells requires B lymphocytes, and that this induction process is dependent on Igh-linked gene products.

Animals↗
PubMed1985

H-2-restricted helper activity mediated by immunoglobulin-bearing lymphocytes.

The genetic requirements for helper activity mediated by a unique, Ig-bearing lymphocyte population were studied. This Lyt-1+, I-A+, Thy-1- population, called BH, preferentially helps expression of NPb idiotypic plaque-forming cells when added to T cell-depleted responder cultures. Furthermore, the BH population can directly bind NPb idiotypic determinants. Using H-2 congenic mice, we show that BH helper activity can be expressed only when BH cells share I-A subregion alleles with responder B cell populations. This H-2 restriction is not a result of thymic influences, because the activity of BH cells from athymic mice are also H-2 restricted. Macrophages present in the BH population do not contribute to the H-2 restriction. Results are presented that definitively rule out the possible role for T lymphocytes in BH activity and demonstrate that a single helper population expresses both Lyt-1 and I-A determinants. These results indicate that Ig-bearing cells serve a regulatory as well as an effector role in immune responses and that, like other regulatory lymphoid subsets, their activity is regulated in part by MHC-encoded determinants.

Animals↗
PubMed1984

An idiotype-specific helper population that bears immunoglobulin, Ia, and Lyt-1 determinants.

A helper cell population with phenotypic characteristics of both B and T cells is described. This helper population, called BH, is present in normal unprimed C57BL/6 mice and preferentially helps the expression of NPb idiotype-bearing plaque-forming B cells in the absence of T helper cells. Its surface phenotype is Lyt-1.2+, Ig+, Lyb-3+, Thy-1.2-, Lyt-2.2-. The helper activity of the BH population is IgH restricted and BH cells selectively bind NPb idiotypic determinants. Collectively the data demonstrate that this unique subpopulation can regulate the response of antibody-secreting B cells through specific recognition of idiotypic determinants.

Animals↗
PubMed1984

Characterization of anti-idiotypic suppressor T cells (Tsid) induced after antigen priming.

The induction and fine specificity of idiotype-specific suppressor T cells (Tsid) were studied. Spleen cells from C57BL/6 mice, immunized 4 wk previously with NP-KLH, failed to express NPb3 idiotype-bearing PFC when challenged in vitro with NP-Ficoll or NP-Brucella abortus. After treatment of NP-primed responder cultures with anti-Thy-1.2 anti-serum + C, NPb idiotype-bearing B cells could be detected. This B cell subset was preferentially suppressed by the addition of T cells from NP-primed mice. With this reconstitution protocol, it was determined that suppression of the NPb idiotype-bearing portion of the B cell response was mediated by a specifically induced T cell population (Tsid) that directly suppressed NPb-bearing B cells. As with a previously described suppressor population induced with hapten-modified syngeneic spleen cells (Ts2), the Tsid population bound and was lysed by NPb idiotype-bearing serum antibodies. However, the Tsid could be distinguished from the Ts2 population because it lacked I-J determinants and functioned as an effector T cell, not an intermediary suppressor cell. Furthermore, fine specificity studies with monoclonal NP-specific antibodies expressing various levels of serologically detectable NPb idiotypic determinants indicated that unlike the Ts2, the Tsid population reacts with conventional, serologically detected members of the NPb family. The combined idiotype binding studies for the Tsid and Ts2 populations demonstrate that the fine specificity of suppressor T cell populations reflects their independent mechanisms of regulation.

Animals↗
PubMed1984

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. XIV. Carrier requirement for suppressor cell induction.

The carrier requirements for the induction of helper and suppressor T (Ts) cells were compared. Although H-2-linked Ir genes control the development of helper T cells and hapten-specific B cells, they do not influence Ts3 generation. That is, GL phi nonresponder C57BL/6 mice can generate NP-specific Ts3 cells after priming with NP-GL phi. The Ts3 cells generated under these conditions are functionally and phenotypically identical to the NP-specific Ts3 cells previously characterized. Furthermore, these Ts3 populations can be specifically depleted with a monoclonal anti-idiotope antibody prepared against monoclonal anti-NP antibodies. By using related polymers, carrier effects on Ts3 induction were noted. NP-D-GL and NP-Ficoll failed to induce Ts3 cells, whereas NP-L-GL induced this suppressor subset. The data demonstrate that Ts3 induction is independent of the carrier requirements involved in helper T cell induction and is not dependent upon B cell priming. The implications of these results with regard to the mechanisms of Ts3 induction are discussed.

Animals↗
PubMed1983

Analysis of T cell hybridomas. III. Distinctions between two types of hapten-specific suppressor factors that affect plaque-forming cell responses.

The ability of two cloned T cell hybridomas and their products to specifically suppress the in vitro plaque-forming cell (PFC) response to the 4-hydroxy-3-nitrophenyl acetyl hapten (NP) was studied. Supernatant from one hybridoma (TS1) was shown to suppress in the induction but not the effector phase of the immune response. Supernatant from the TS1 hybridoma was capable of inducing second-order (TS2) effector-phase suppressor cells in vitro but did not suppress the response of anti-I-J plus C-treated responder cells. In contrast, supernatant from a second hybridoma (TS3) was capable of suppressing PFC responses when added either in the induction or the effector phase of the response. TS3 supernatant was unable to induce effector-phase suppressor cells but was capable of suppressing the response of anti-I-J plus C-treated responder cells. In addition, specific suppressor factors isolated from supernatants of the TS1 and TS3 hybridomas were shown to bind to NP, bear NPb idiotypic and I-J-encoded but not immunoglobulin-constant region determinants. The factor secreted by the TS3 hybridoma appears to act directly on B cell targets. Mild reduction of this factor results in two separable moieties, only one of which binds NP. Reconstitution experiments suggest that both chains are required for function. The collective data indicate that these hybridomas represent cells from first- and third-order suppressor T cell populations described previously in contact sensitivity and in vitro PFC systems. The implications of the ability of these hybridoma products to affect both T and B cell-mediated immune responses are discussed.

Animals↗
PubMed1982

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. XIII. Characterization of a third T cell population involved in suppression of in vitro PFC responses.

The involvement of a third-order suppressor T cell population (Ts3) in the suppression of in vitro PFC responses was analyzed. It was shown that Ts2 effector-phase suppressor cells, induced by the i.v. injection of NP-coupled syngeneic spleen cells, require a third suppressor T cell population to effect NPb idiotype-specific suppression of an in vitro B cell response. This Ts3 population was shown to be present in NP-primed but not unprimed donors. The Ts3 population specifically binds NP and is Lyt-1-, Lyt-2+, I-J+ and bears NPb idiotypic determinants. The involvement of the Ts3 population in a suppressor pathway that requires recognition of idiotypic determinants is discussed.

Animals↗
PubMed1981

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. XII. Fine specificity of anti-idiotypic suppressor T cells (Ts2).

The fine specificity of anti-idiotypic, effector-phase suppressor T cells (Ts2) induced by the intravenous injection of syngeneic spleen cells covalently coupled with the 4-hydroxy-3-nitrophenyl acetyl (NP) hapten was studied in an in vitro plaque-forming cell system. By comparing the ability of these suppressor cells to bind monoclonal anti-NP antibodies that express different levels of serologically detected NPb idiotypic determinants, it was shown that anti-idiotypic suppressor T cells do not recognize the predominant NPb idiotypic determinants that are defined by serologic analysis. The implications for the possible expression and/or recognition of different sets of idiotypic determinants on T and B cells are discussed.

Animals↗
PubMed1981

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. XI. Pseudogenetic restrictions of hybridoma suppressor factors.

Suppressor factor derived from three different murine T cell hybridomas were characterized . They specifically inhibited 4-hydroxy-3-nitrophenyl acetyl cutaneous sensitivity responses. The factors bind antigen and bear I-J and idiotypic determinants, but lack conventional immunoglobulin constant-region determinants. The factors function during the induction phase of the immune response, by inducing a second population of suppressor cells (Ts(e)). Suppressor factor can inhibit both cellular and plaque-forming cell responses in appropriate strains of mice. These hybridoma suppressor factors directly suppress strains of mice that are Igh-V homologous with the strain producing the factor. Thus, there is an apparent Igh-V restriction in the activity of these factors. However, this is a pseudogenetic restriction because these factors generate second order suppressor cells (Ts(e)) in Igh-incompatible mice, but in order to express the suppressive activity, the cells must be adoptively transferred into recipients that are Igh compatible with the strain producing the suppressor factor. Finally, it was shown that the factor-induced Ts(e) population is under an apparent dual genetic restriction. Thus, Igh and H-2 homology is required in order for the Ts(e) population to express its suppressive activity.

Antibody Formation↗
PubMed1981

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. IX. Characterization of Idiotype-specific effector-phase suppressor cells on plaque-forming cell responses in vitro.

The ability of T suppressor cells, induced by the intravenous injection of 4-hydroxy-3-nitrophenyl acetyl (NP)-modified syngeneic spleen cells, to affect an ongoing B cell response was studied in vitro. It was found that the expression of NPb idiotype-positive B cells could be selectively inhibited by the addition of antigen-induced suppressor cells in the last 24 h of the in vitro culture. This effector-phase suppression of B cell responses was antigen specific and mediated by an Lyt 1-, Lyt 2+, idiotype-binding, T cell population whose suppressive function was restricted by genes linked to the Igh locus.

Animals↗
PubMed1981

Hapten-specific T cell responses to 4-hydroxy-3-nitrophenyl acetyl. VII. Idiotype-specific suppression of plaque-forming cell responses.

The ability of suppressor cells induced by the intravenous administration of 4-hydro-3-nitrophenyl acetyl (NP)-modified syngeneic cells to reduce an idiotypic B cell response was studied in both an in vivo and an in vitro system. Idiotype-positive B cells were assayed by the ability of guinea pig anti-idiotypic antiserum to specifically inhibit idiotype-positive plaque formation. It was found that up to 57% of the PFC response in vivo and 100% of the PFC response in vitro was inhibitable with antiidiotypic antiserum. The expression of these idiotype-positive B cells could be suppressed by the transfer of spleen cells form mice treated 7 d previously with NP coupled syngeneic cels. T cells are both required and sufficient for the transfer of idiotype specific suppression. The induction of these idiotype-specific T suppressor cells directly with antigen suggests that recognition of unique determinants on cell surfaces is important for regulation of lymphoid cell interactions. The role of idiotype-specific suppressor cells in the network of lymphoid interactions is discussed.

Animals↗
PubMed1981

Effect of anti-Lyb3 antiserum on poly (L-glutamic acid, L-lysine)-induced B cell tolerance.

The effect of anti-Lyb3 antiserum on antigen-specific B cell tolerance was investigated. The intraperitoneal injection of the nonimmunogenic copolymer L-glutamic acid60, L-lysine (GL) specifically reduces the ability of murine B cells to form GL-specific plaque-forming cell responses following challenge with the immunogenic conjugate of GL coupled to fowl gamma-globulin. It was found that this tolerance could be reversed or blocked by the intravenous injection of microliter quantities of anti-Lyb3 antiserum. However, this dose of antiserum neither reversed T cell tolerance induced with protein-coupled syngeneic erythrocytes nor induced tolerized B cells to secrete antibody. The results suggest that B lymphocytes can be rescued from GL-induced tolerance soon after induction and that Lyb3 determinants may play a functional role in the activation of antigen-specific B lymphocytes.

Animals↗
PubMed1980

Immune suppression in vivo with antigen-modified syngeneic cells. V. Interacting T cell subpopulations in the suppressor pathway.

Intravenous administration of syngeneic C57BL/6 cells coupled with the palmitoyl derivative of the protein antigen fowl gamma-globulin (p-FgG) results in a state of FgG carrier-specific nonresponsiveness, mediated in part by suppressor T cells. At least two populations of cells are involved in generating a suppressor pathway in this system, one induced in recipients of p-FgG coupled cells and the other contributed by normal recipients of cells from suppressed donors. Induction of T cells capable of transferring suppression to normal recipients is sensitive to 1) low doses of cyclophosphamide, 2) adult thymectomy, and 3) in vivo treatment with anti-I-J antisera. This T cell subset bears I-J determinants and is functionally sensitive to irradiation. The induction of the second population required for immune suppression is sensitive to 1) low doses of cyclophosphamide and 2) adult thymectomy. In addition, compatibility of genes at the Igh locus appears not to be essential for cellular interaction between these populations. The evidence that interacting T cell subpopulations are involved in a suppressor pathway induced with protein-modified syngeneic cells is discussed relative to other systems in which T-T cell interactions are postulated.

Animals↗
PubMed1979

Ontogeny of B-lymphocyte function. IX. Difference in the time of maturation of the capacity of B lymphocytes from foetal and neonatal mice to produce a heterogeneous antibody response to thymic-dependent and thymic-independent antigens.

The ontogeny of the capacity of the B-lymphocyte population to produce a response which is heterogeneous with respect to antibody affinity was studied in a cell transfer system. Lethally irradiated mice were reconstituted with B cells from donors of various ages, together with adult thymus cells when the response to T-dependent antigens was studied. The animals were immunized with one of a variety of antigens one day after cell transfer and the distribution of their splenic plaque-forming cells (PFC) with respect to affinity was assayed, by hapten inhibition of plaque formation, 2 to 3 weeks after immunization. Mice reconstituted with B cells from neonatal donors produced a response of low affinity and restricted heterogeneity. With four different thymic-dependent antigens (DNP-BGG, F-BGG, DNP-KLH and Dan-KLH) the splenic B-cell population acquired the capacity to reconstitute irradiated mice to produce a normal adult-like, highly heterogeneous, high affinity PFC response between 7 and 10 days after birth. The capacity to produce a heterogeneous response to the thymic-dependent protein antigen BGG matured just slightly later between 10 and 14 days of age. The bone marrow matures with regard to the capacity to reconstitute irradiated mice to give a heterogeneous response several days after the spleen, possibly as a consequence of the redistribution of peripheral B cells to the bone marrow. In contrast, maturation of the capacity of the splenic B-cell population to reconstitute irradiated recipients to give a heterogeneous, adult-like PFC response to three 'thymic-independent' antigens (TNP-PA, DNP-Ficoll and TNP-BA) takes place considerably later (between 3 and 4 weeks of age). These results suggest that the population of B-cell precursors which responds to thymic-dependent antigens may represent a different subpopulation of B cells from the population that responds to thymic independent antigens. Furthermore, the results suggest that these B-cell subsets mature at different times, presumably under independent controls.

Age Factors↗