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R J Hodes

Publications and source records attributed to R J Hodes.

At least 127 records · Page 7Linked to original sources
PubMed1985

Lyb-5+ B cells can be activated by major histocompatibility complex-restricted as well as unrestricted activation pathways.

It has previously been demonstrated that B cells can be activated through two distinct T helper (Th) cell-dependent pathways, one requiring both carrier-hapten linkage and MHC-restricted T-B interaction and the other requiring neither. In addition, it has been shown that different B cell subpopulations exist and that these subpopulations differ in their activation requirements. Previous studies demonstrated that resting B cells containing an Lyb-5+ subpopulation were activated by MHC-unrestricted T cell signals, whereas resting Lyb-5- B cells were activated only through MHC-restricted T-B interaction. It was suggested that this difference resulted from the ability of Lyb-5+ but not Lyb-5-B cells to respond to soluble MHC-unrestricted Th signals. Because Lyb-5+ B cells were responsive in these previous experiments to MHC-unrestricted Th signals, it could not be determined whether Lyb-5+ B cells were also responsive to MHC-restricted Th signals. Consequently, the present study was undertaken to directly address the question of whether Lyb-5+ B cells can be activated under appropriate conditions by MHC-restricted as well as unrestricted T cell-B cell interactions. It was found that unprimed normal B cells (containing Lyb-5+ and Lyb-5-B cells) but not unprimed xid-defective populations (Lyb-5- only) can be activated by cloned KLH-specific and MHC-restricted Th cells in response to either high or low concentrations of TNP-KLH. The IgM response of Lyb-5+-containing B cells to a high concentration of antigen (10 micrograms/ml) was MHC unrestricted, whereas the IgM response of unprimed Lyb-5+ B cells to a low concentration of antigen (0.001 micrograms/ml) was MHC restricted. Thus, unprimed Lyb-5+ B cells can be activated through both MHC-restricted and unrestricted pathways. It was further demonstrated that the activation requirements of Lyb-5+ and Lyb-5- B cells differed even for MHC-restricted B cell activation.

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PubMed1984

T cell regulation of B cell activation: MHC-restricted T augmenting cells enhance the B cell responses mediated by MHC-restricted cloned T helper cells.

The present studies demonstrated that unprimed populations of Lyt-1+2- T cells are able to augment the responses generated by optimal numbers of antigen-specific and MHC-restricted cloned TH cells. The TA cells function early in the course of B cell responses. Responses mediated by (A X B)F1 (B + accessory) cells and parentA restricted cloned TH cells are augmented by TA cells from (A X B)F1 leads to parentA radiation bone marrow chimeras, but not by TA cells from (A X B)F1 leads to parentB chimeras. Thus, TA cell activation and function are MHC-restricted, but this restriction is not related to recognition of genotypically expressed B cell and/or accessory cell MHC products alone. Rather, TA cell function is intimately related to the MHC-restricted interaction between TH cells and responding (B + accessory) cells. Specifically, it was shown that TH cell interaction with B cells via an MHC-restricted and carrier-hapten-linked pathway is required for the function of TA cells expressing the same MHC restriction. Moreover, neither MHC homology nor TH cell recognition of MHC determinants on TA cells is required for TA cell function, and the activity of TA cells is not demonstrably influenced by non-MHC genes. It was further demonstrated that the function of cloned TH cells in B cell activation consists of at least two distinct components, one is radiosensitive and the other is radioresistant. TA cells are able either to replace the radiosensitive function of cloned TH cells directly or to bypass this requirement through an alternative pathway.

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PubMed1984

Generation of the alloreactive T cell repertoire: K region homology between H-2b T cell precursors and T cell maturation environment is required for the generation of the Kbm6-specific cytotoxic T cell repertoire.

The influence of T cell genotype and T cell maturation environment on the generation of the T cell alloreactive repertoire was evaluated in the H-2b cytotoxic T lymphocyte response to Kb mutant determinants expressed by the strain B6-H-2bm6. Specifically, by constructing radiation bone marrow chimeras with B6 or B10 (H-2b) donor cells and B10.BR, B10.A(4R), B10.MBR, and B6.C-H-2bm1 irradiated mice as recipients, it was possible to investigate the major histocompatibility complex (MHC)-encoded gene products of the host environment required for the generation of a bm6-specific H-2b CTL response. The results of such experiments confirmed the previous finding that the alloreactive T cell repertoire is influenced both by T cell MHC genotype and by the MHC gene products of the T cell maturation environment. In addition, the results of the present study further demonstrated that in the chimeric donor and host genetic combinations used, it was both necessary and sufficient that there be a homology of K region-encoded determinants for the generation of a bm6-specific CTL response. Experiments utilizing a mixed responder population of unresponsive B6----B10.D2 spleen cells and responsive Lyt-2 congenic B6.Lyt-2.1 spleen cell suggested that the cellular defect(s) underlying the unresponsiveness of the chimeric cells to bm6-encoded determinants was at the level of the CTL precursor. Together, these findings indicate that an interaction of the K region-encoded gene products of the T cell and its maturation environment play a critical role in the generation of the CTL repertoire specific for bm6 mutant determinants. We discuss here the possibility that this interaction may reflect a requirement that T cells recognize such mutant allodeterminants in association with self restriction elements present on the same mutant K region-encoded molecule.

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PubMed1984

Activation of B cells by autoreactive T cells: cloned autoreactive T cells activate B cells by two distinct pathways.

Although the existence of autoreactive T cells has been widely reported, the functional capacities of these populations have been less well defined. Studies were therefore carried out to characterize the relationship of autoreactive T cells to antigen-specific major histocompatibility complex (MHC)-restricted T cells in their ability to act as helper cells for the induction of immunoglobulin synthesis by B cells. A number of autoreactive T cell lines and clones were isolated from antigen-primed spleen and lymph node cell populations. Autoreactive T cells were found to proliferate in response to direct recognition of syngeneic I-A or I-E subregion-encoded antigens in the absence of any apparent foreign antigen. It was shown that cloned autoreactive T cells were capable of activating B cell responses through two distinct pathways. After appropriate stimulation by syngeneic cells, autoreactive T cells polyclonally activated primed or unprimed B cells to synthesize IgM antibodies. These activated T cells functioned in these responses through an MHC-unrestricted pathway in which polyclonal responses were induced in both syngeneic and allogeneic B cells. These cloned autoreactive T cells were also able to activate IgG responses by primed B cells through a different activation pathway. In contrast to the polyclonal activation of IgM responses, the induction of IgG antibodies by the same cloned T cells required primed B cells and stimulation with the priming antigen. The activation of B cells to produce IgG was strongly MHC restricted and required the direct recognition by the autoreactive T cells of self MHC determinants expressed on the B cell surface, with no bystander activation of allogeneic B cells. These results indicate that cloned autoreactive T cells resemble antigen-specific MHC-restricted T cells in their ability to function as T helper cells through distinct MHC-restricted and MHC-unrestricted pathways.

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PubMed1984

An analysis of functional T cell recognition sites on I-E molecules.

The recognition of I-E molecules by antigen-specific T cells was studied to determine if one or multiple topographic sites on the I-E molecules can function as restricting elements for T cells. A panel of 14 I-Ek-specific monoclonal antibodies (mAb) was used to inhibit T cell proliferation induced by antigens, the recognition of which was restricted by I-E-encoded determinants. These antibodies gave patterns of inhibition that were similar for three long-term antigen-specific T cell lines. Multiple distinct patterns of inhibition, however, were observed when a series of antigen-specific I-E-restricted T cell clones was studied. Differences were identified even among clones expressing apparently similar antigen specificities and MHC restriction. The observed inhibition by these antibodies appeared to be caused by specific steric or allosteric interference with T cell recognition of antigen and Ia. Based on the differences in patterns of inhibition, it was possible to infer the existence of distinct sites or conformations on the I-E molecule that are functionally involved in antigen-specific T cell recognition.

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PubMed1984

Recognition and response to alloantigens in vivo. II. Priming with accessory cell-depleted donor allogeneic splenocytes: induction of specific unresponsiveness to foreign major histocompatibility complex determinants.

Although the role of non-T, non-B Ia+ accessory cells as the cells that stimulate alloreactive T cells in vitro has been carefully examined, the capacity of such accessory cells to trigger host T cells in vivo has been considerably less well studied. Therefore, to address the latter issue, this investigation compared the ability of accessory cell-containing and accessory cell-depleted donor cells to mediate in vivo negative and positive selection of mixed lymphocyte reaction (MLR)-responsive peripheral blood lymphocytes (PBL). It was observed that both unseparated and accessory cell-depleted (Sephadex G-10-passed) allogeneic splenocytes, which expressed similar levels of Ia antigens as detected by flow cytometry, were equally efficient in inducing temporary specific unresponsiveness to alloantigens in host PBL 24 hr after donor cell injection. In contrast, 4 days after priming with unseparated major histocompatibility complex (MHC)-incompatible splenocytes, specific MLR hyperresponsiveness was detected in the PBL of these recipient mice, whereas specific hyporesponsiveness was consistently noted in animals injected with accessory-cell depleted splenocytes. PBL obtained from this latter group of mice continued to be specifically reduced in MLR proliferative capacity throughout the culture period and for at least 13 days after administration of accessory cell-depleted allogeneic splenocytes. Mixture of these MLR hyporesponsive and hyperresponsive PBL did not identify suppressor cells as responsible for the specifically lowered proliferative potential. These findings are discussed in the context of discrete signals required for T cell recognition and T cell activation.

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PubMed1984

T cell regulation of B cell activation. An antigen-mediated tripartite interaction of Ts cells, Th cells, and B cells is required for suppression.

To determine the requirements underlying the antigen specificity observed in T cell-mediated immune response suppression, cloned major histocompatibility complex (MHC)-restricted T suppressor (Ts) cells specific for keyhole limpet hemocyanin (KLH) and cloned MHC-restricted T helper (Th) cells specific for fowl gamma-globulin (FGG) were employed to study the regulation of trinitrophenyl (TNP)-specific B cell responses. Neither antigen bridging between Ts cells and Th cells (FGG=KLH) nor bridging between Ts cells and B cells (TNP-KLH) was sufficient to allow suppression; a mixture of FGG=KLH and TNP-KLH was also insufficient for suppression. In contrast, suppression was induced by KLH-specific Ts cells only when suppressor determinants (KLH), helper determinants (FGG), and B cell determinants (TNP) were covalently linked on the same molecule (TMP-FGG)=(TNP-KLH) or TNP-(FGG=KLH)). These findings imply that a tripartite antigen-mediated interaction of Ts cells, Th cells, and responding B cells is necessary for the mediation of this antigen-specific suppression.

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PubMed1983

T cell regulation of b cell activation. Cloned Lyt-1+2-T suppressor cells inhibit the major histocompatibility complex-restricted interaction of T helper cells with B cells and/or accessory cells.

The present studies have identified cloned Lyt-1+2- T suppressor (Ts) cells that are both antigen specific and major histocompatibility complex (MHC) restricted in their activation requirements and that function to regulate the MHC-restricted activation of B cells by T helper (Th) cells. ParentA-restricted Ts clones suppressed, in antigen-specific fashion, the responses generated by (A X B)F1 Th cells cooperating with parentA (B plus accessory) cells, but did not suppress responses by the same (A X B)F1 Th cell population cooperating with parentB (B plus accessory) cells. Moreover, responses of (A X B)F1 leads to parentA Th cells and (A X B)F1 (B plus accessory) cells were suppressed by parentA-restricted Ts clones but not by parentB-restricted Ts clones. Thus, these findings suggest that the cloned Ts cells that have been characterized here function by specifically inhibiting the MHC-restricted interaction between Th cells and B and/or accessory cells. It was further demonstrated in experiments using cloned Th and Ts populations that these Lyt-1+2-Ts cells act not simply as inducers of suppressor but rather function in a restricted fashion as effector cells in the suppressor pathway.

Animals↗
PubMed1983

T cell regulation of B cell activation. I-A-restricted T suppressor cells inhibit the major histocompatibility complex-restricted interactions of T helper cells with B cells and accessory cells.

The present studies were carried out to characterize the cellular interactions involved in the activation and function of the antigen-specific and antigen-nonspecific T suppressor (Ts) cells that regulate the IgG responses of Lyb-5-B cells. The in vitro activation of both Lyt-1+2- antigen-nonspecific Ts cells and Lyt-1-2+ antigen-specific Ts cells was shown to require the interaction of accessory cells and antigen-primed T cells. It was further demonstrated that this interaction was major histocompatibility complex (MHC)-restricted in that T cell recognition of I-A-encoded determinants on accessory cells was required for Ts cell activation. The activation of antigen-primed (A X B)F1 T cells with antigen in the presence of parentA or parentB accessory cells resulted, respectively, in the generation of parentA-restricted or parentB-restricted Ts cells. ParentA-restricted F1 Ts cells suppressed the responses generated by (A X B)F1 T helper (Th) cells cooperating with parentA (B + accessory) cells but did not suppress responses by the same (A X B)F1 Th cell population cooperating with parentB (B + accessory) cells. Neither parentA-restricted Ts cells alone nor parentB-restricted Ts cells alone suppressed the responses of (A X B)F1 (B + accessory) cells, whereas a mixture of these two Ts cell populations was able to significantly suppress the responses of F1 (B + accessory) cells. In contrast, responses of (A X B)F1 leads to parentA Th cells (restricted to recognizing parentA but not parentB MHC determinants on F1 cells) and (A X B)F1 (B + accessory) cells was suppressed by parentA-restricted Ts cells but not by parentB-restricted Ts cells. Collectively these findings suggest that the Ts cell populations characterized here do not function by directly inhibiting the activity of Th cells, B cells or accessory cells of a given MHC genotype, but rather that they appear to function through a unique mechanism involving highly specific inhibition of the interaction between MHC-restricted Th cells and the (B + accessory) cells required for these responses.

Animals↗
PubMed1983

Major histocompatibility complex-restricted self-recognition in responses to trinitrophenyl-Ficoll. A novel cell interaction pathway requiring self-recognition of accessory cell H-2 determinants by both T cells and B cells.

In vitro primary antibody responses to limiting concentrations of trinitrophenyl (TNP)-Ficoll were shown to be T cell dependent, requiring the cooperation of T helper (TH) cells, B cells, and accessory cells. Under these conditions, TH cells derived from long-term radiation bone marrow chimeras were major histocompatibility complex (MHC) restricted in their ability to cooperate with accessory cells expressing host-type MHC determinants. The requirement for MHC-restricted self-recognition by TNP-Ficoll-reactive B cells was assessed under these T-dependent conditions. In the presence of competent TH cells, chimeric B cells were found to be MHC restricted, cooperating only with accessory cells that expressed host-type MHC products. In contrast, the soluble products of certain monoclonal T cell lines were able to directly activate B cells in response to TNP-Ficoll, bypassing any requirement for MHC-restricted self-recognition. These findings demonstrate the existence of a novel cell interaction pathway in which B cells as well as TH cells are each required to recognize self-MHC determinants on accessory cells, but are not required to recognize each other. They further demonstrate that the requirement for self-recognition by B cells may be bypassed in certain T-dependent activation pathways.

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PubMed1983

Regulatory mechanisms in cell-mediated immune response. V. Distinct Lyt subsets mediate antigen-specific and antigen-nonspecific suppression.

These studies were undertaken to assess the T cell subpopulations mediating antigen-specific as well as antigen-nonspecific suppression of cytotoxic T lymphocyte (CTL) responses to alloantigens. It was first demonstrated that generation of the CTL response itself requires Lyt 1+2+ T cells. Subsequent studies then characterized two distinct suppressor pathways that regulate the CTL response. Antigen nonspecific suppression was mediated by Lyt 1+2-Ts cells that were generated during in vitro culture from an Lyt 1+2- precursor population. In a second pathway, antigen-specific suppression was mediated predominantly by Lyt 1-2+ Ts cells that were activated during the in vitro allosensitization of Lyt 1+2+ precursors. Thus, the in vitro CTL response to alloantigens is modulated by two different pathways of T-cell-mediated suppression, and these pathways are mediated by distinct Lyt-defined T cell subpopulations.

Animals↗
PubMed1983

T cell regulation of B cell activation: antigen-specific and antigen-nonspecific suppressor pathways are mediated by distinct T cell subpopulations.

The present studies were carried out to characterize the cellular events involved in the induction and function of carrier-specific Ts cells, which selectively regulate the generation of IgG responses by Lyb-5- B cells. It was demonstrated that this regulation is in fact mediated by two distinct suppressor pathways. In one pathway, carrier-primed Lyt-1 + 2 - Ts cells are specifically activated by in vitro reexposure to the priming antigen. After this specific activation, these Lyt-1 + 2 - Ts cells are able to suppress IgG responses in an antigen-nonspecific manner. This suppression requires the participation of unprimed Lyt-1 - 2 + T cells, and is effective in both the early and the late phases of antibody responses. A second suppressor pathway requires the antigen-specific activation of primed Lyt-1 - 2 + Ts cells. Suppression of antibody responses by activated Lyt-1 - 2 + Ts cells is highly carrier specific, in contrast to the nonspecific effector function of Lyt-1 + 2 - Ts cells, appears to act without requirement for additional T cell populations; and is effective only early in the course of the antibody response. Thus, it appears that two Ts cell populations may function through distinct mechanisms to regulate the generation of IgG Lyb-5- B cell responses.

Animals↗
PubMed1983

Role of the major histocompatibility complex in T cell activation of B cell subpopulations. Ir gene regulation of the T cell-dependent activation of distinct B cell subpopulations.

Antibody responses to (T,G)-A--L and (H,G)-A--L or to the TNP conjugates of these polypeptides, are regulated in the mouse by Ir genes encoded in the I-A subregion of the mouse MHC. To study the mechanism by which Ir genes function, it is essential to identify the cell interactions that are regulated by these genes. In the present report, it was specifically determined whether Ir gene function is expressed differently in the activation of B cell subpopulations that participate in two different pathways of B cell activation for in vitro antibody responses to TNP-(T,G)-A--L and TNP- (H,G)-A--L. The results of these studies demonstrate that under conditions that activate the Lyb-5- b cell subpopulation via MHC-restricted TH cell-B cell and TH cell-APC interactions, Ir gene function regulates TH cell interactions with these B cells as well as with APC. In addition, under conditions that activate the Lyb-5+ B cell subpopulation via MHC-restricted TH cell-APC but not TH cell-B cell interaction, Ir gene function regulates only TH cell interactions with APC but not with B cells.

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PubMed1982

Major histocompatibility complex-restricted self-recognition in responses to trinitrophenyl-ficoll. Adaptive differentiation and self-recognition by B cells.

The present study has examined the possibility of TNP-Ficoll-responsive B cells recognize the MHC determinants expressed by the accessory cells with which they interact for the generation of T cell-independent responses to "high" concentrations (10(-2) micrograms/ml) of TNP-Ficoll. In experiments with B cells from normal mice, it was found that MHC homology between the TNP-Ficoll-responsive B cells and accessory cells was not required. Nevertheless, TNP-Ficoll-responsive B cells from both fully allogeneic (A leads to B) and F1 leads to parent radiation bone marrow chimeras were triggered by accessory cells expressing host-type, but not uniquely donor-type, MHC determinants. The MHC gene products responsible for this apparent B cell-accessory restriction were encoded in the left side, i.e., the K and/or I-A region, of H-2. Such genetic restrictions were shown not to be imposed by the residual T cells contaminating the chimeric B cell populations because T cell reconstitution experiments using "unrestricted" F1 T cells from normal mice did not fully overcome the marked preference of the chimeric B cells for accessory cells expressing appropriate (host-type) MHC determinants. To directly determine whether TNP-Ficoll-responsive B cells from fully allogeneic chimeras are unable to recognize and cooperate with syngeneic strain A accessory cells, unfractionated spleen cells from A leads to B chimeras are co-cultured with unfractionated spleen cells from essentially syngeneic normal strain A mice. In such co-cultures, all the accessory cells express strain A MHC determinants, and all T cell requirements would be fulfilled by the T cells present in the normal strain A spleen cell population. After stimulation of the co-cultures with TNP-Ficoll, it was found that virtually all the PFC that had been generated in the co-cultures were derived from the normal B cell population, and essentially none were derived from the chimeric A leads to B B cell population. The failure of the chimeric B cells to be activated in such co-cultures was specifically due to their maturation in a fully allogeneic host environment because TNP-Ficoll-responsive B cells from A leads to (A X B) F1 chimeric mice were successfully triggered in co-cultures with normal spleen cells. These experiments demonstrated that the co-culture conditions did fulfill the MHC restriction requirements for activating TNP-Ficoll-responsive strain A B cells that had matured in a syngeneic or semi-syngeneic differentiation environment, but did not fulfill the MHC restriction requirements for activating TNP-Ficoll-responsive strain A B cells that had matured in a fully allogeneic differentiation environment. Taken together, these results demonstrate that (a) TNP-Ficoll-responsive B cells recognize the MHC determinants expressed by accessory cells, and (b) their MHC specificity is influenced by the MHC haplotype of the host environment in which the B cells had differentiated.

Animals↗
PubMed1982

Role of the major histocompatibility complex in T cell activation of B cell subpopulations. A single monoclonal T helper cell population activates different B cell subpopulations by distinct pathways.

It has recently been demonstrated that the Lyb-5+ and Lyb-5- B cell subpopulations differ in their requirements for major histocompatibility complex (MHC)-restricted activation by T helper (TH) cells. To determine whether these MHC-restricted and -unrestricted pathways of B cell activation result from differences in the participating TH cell populations or reflect differences exclusively in the responding B cell subpopulations, experiments were carried out using cloned TH cells for in vitro antibody responses to trinitrophenyl-keyhole limpet hemocyanin. The same cloned T helper cells were able to activate both CBA/N (Lyb-5-) B cells and CBA/CaHN (Lyb-5+ + Lyb-5-) B cells under different experimental conditions. The activation of Lyb-5-B cells by cloned T helper cells required both MHC-restricted TH cell-B cell interaction and carrier-hapten linkage. In contrast, the activation of Lyb-5+ B cells required only MHC-restricted T helper cell interaction with accessory cells, while T-B interaction was MHC unrestricted and did not require carrier-hapten linkage. Thus, the differences in activation requirements observed for the Lyb-5- and Lyb-5+ B cell subsets do not result from differences in the TH cell populations activating these B cells, but rather reflect differences in the ability of these B cells to respond to signals from the same TH cells.

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PubMed1982

T cells from fully H-2 allogeneic (A replaced by B) radiation bone marrow chimeras are functionally competent and host restricted but are alloreactive against hybrid Ia determinants expressed on (A x B)F1 cells.

In this communication it is demonstrated that T cells from fully allogeneic A replaced by B radiation bone marrow chimeras are alloreactive against the hybrid Ia molecules expressed on the surface of heterozygous A X B cells. These results suggested that previous failures to generate cytotoxic T lymphocyte (CTL) responses from fully allogeneic chimeras by sensitizing the chimeric T cells to antigen in an (A X B)F1-priming environment might have been confounded by an ongoing alloreaction against determinants created by hybrid Ia molecules expressed on F1 cells. Consequently, the ability to generate CTL responses from fully allogeneic chimeras was re-examined by sensitizing the chimeric T cells to antigen presented by homozygous rather that F1 stimulator cells. It was found that T cells of donor bone marrow origin that mediate cytotoxic responses to trinitrophenyl-modified self determinants do differentiate into functional competence in an H-2-incompatible host environment and are restricted to the host H-2 haplotype.

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