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A K Abbas

Publications and source records attributed to A K Abbas.

At least 73 records · Page 4Linked to original sources
PubMed1992

Antigen receptor-mediated anergy in resting T lymphocytes and T cell clones. Correlation with lymphokine secretion patterns.

The goal of these studies was to define the stimuli and factors that control the induction of anergy in unimmunized resting T lymphocytes. Initial experiments, aimed at establishing the system, showed that exposure of Th1 but not Th2 clones to immobilized anti-CD3 leads to a block in autocrine growth factor production and proliferation upon subsequent restimulation with Ag+APC. Anergy is not prevented by accessory cells, suggesting that this model of T cell tolerance may be due to receptor-mediated inhibitory signals, independent of costimulatory molecules. Culture of small (resting) unimmunized T lymphocytes with anti-CD3 +/- IL-2 induces unresponsiveness to restimulation with anti-CD3, but culture with anti-CD3+IL-4, which stimulates the differentiation of resting cells into IL-4 producers, does not induce anergy. Thus, IL-4-producing clones and bulk populations of IL-4-producing T cells are resistant to Ag receptor-mediated inhibitory stimuli. These results provide experimental models for studying the mechanisms of anergy in normal, unselected, mature T cells, and demonstrate fundamental similarities between cloned cell lines and unimmunized T lymphocytes in the induction of anergy.

Animals↗
PubMed1992

Aqueous antigens induce in vivo tolerance selectively in IL-2- and IFN-gamma-producing (Th1) cells.

As a model for understanding in vivo immune responses, we have exposed mice to aqueous haptenated-protein Ag, and examined immune responses to subsequent immunization with Ag in adjuvant. Pretreating mice with soluble, TNP-conjugated Ag induces selective nonresponsiveness to Ag for both humoral and cell-mediated immune functions. Specific T cell proliferation in response to Ag is inhibited, and Ag-induced secretion of the lymphokines IL-2 and IFN-gamma, but not IL-4, is reduced. B cell responses after pretreatment are also affected. Although levels of TNP-specific IgG1 and IgE are similar in treated and untreated mice, soluble Ag pretreatment diminishes production of TNP-specific IgG2a and IgG2b. This is due to lack of T cell help and is not caused by tolerance in the B cell compartment. These results indicate that pretreatment of mice with aqueous Ag induces selective unresponsiveness in Th1-like Th cells, which secrete IL-2 and IFN-gamma, but not in Th2-like Th cells, which secrete IL-4.

Animals↗
PubMed1992

T cell surface molecules regulating noncognate B lymphocyte activation. Role of CD2 and LFA-1.

A central event in humoral responses is the Ag-mediated interaction of Th cells and B cells. This interaction leads to the activation of both cell types and results in cytokine secretion by the T cells and proliferation and secretion of Ig by the B cells. The proliferative and differentiative responses of B cells are dependent on contact-mediated signals and cytokines provided by the activated Th cells. Although the role of cytokines in B cell activation and differentiation is understood, the nature of the signals delivered by the activated Th cells and the molecules involved in this process are not known. In this study we have examined Ag-mediated "cognate" T-B cell interactions as well as B cell activation induced by contact with preactivated and fixed Th lymphocytes. Our results indicate that both the T cell surface molecules lymphocyte function associated Ag-1 and CD2 are important in the activation of T cells by Ag presented by B lymphocytes. This indicates that B cells have similar characteristics as other APC. However, once the T cells are activated, contact-mediated stimulation of resting B lymphocytes (the noncognate phase) is dependent on CD2 but not lymphocyte function associated Ag-1. Two lines of evidence indicate this; first, it is inhibited by blocking of CD2 on the T cells and, second, such stimulation is not efficiently mediated by a CD2- Th cell line. Thus, CD2 plays an obligatory role at several discrete stages of T cell-mediated activation of resting B lymphocytes.

Animals↗
PubMed1992

Association of murine CD31 with transmigrating lymphocytes following antigenic stimulation.

Human CD31 is a recently characterized molecule present on leukocytes, platelets, and endothelium. Its function is not known. Because it is a member of the immunoglobulin superfamily and structurally homologous to carcinoembryonic antigen, a putative intercellular adhesion molecule, it is believed that CD31 may function also as an adhesion molecule. In this report, we characterize the cellular reactivity of a monoclonal antibody to a murine protein that is homologous to CD31. To delineate the cellular reactivity of the murine CD31 homologue recognized by our monoclonal antibody, we used immunoperoxidase and immunoelectron microscopic techniques. The most striking finding was that the putative murine homolog of CD31 is expressed in particularly high amounts on endothelium-adherent lymphocytes transmigrating across sinusoidal or venular vascular boundaries. Such a distribution was apparent in draining murine lymph nodes during the peak of an immune response after immunization with a protein antigen in adjuvant, a situation in which there are many transmigrating lymphocytes. Immunoelectron microscopic analysis also shows that CD31 is predominantly distributed on portions of transmigrating lymphocytes that are in contact with or adjacent to areas of contact with endothelial cells. These findings suggest a previously undescribed role for CD31 in lymphocyte recruitment and transmigration.

Amino Acid Sequence↗
PubMed1991

Humoral immune functions in IL-4 transgenic mice.

We have analyzed mice expressing IL-4 as a transgene, and found that expression of this lymphokine has profound effects on B cell function. B cells from transgenic mice exhibit phenotypic changes, including an increase in size and elevated expression of class II MHC. IL-4 increases the quantity of IgE produced by transgenic-derived B cells in response to LPS stimulation. In vivo, IL-4 markedly affects the serum Ig isotype repertoire. Serum levels of IgG1 and IgE are elevated, and levels of IgG2a, IgG2b, and IgG3 are depressed in IL-4 transgenic mice. Ag-specific antibody responses to immunization with hapten-carrier conjugates are also affected by IL-4. Transgenic mice show increased anti-hapten IgE and IgG1 and reduced anti-hapten IgG2a, IgG2b, and IgG3, compared with wild-type mice. Ag-specific IgE is substantially induced by T cell-dependent Ag, but not T cell-independent Ag, suggesting that cognate T-B interactions in addition to IL-4 are required for generating IgE responses in vivo. In vivo treatment with the anti-IL-4 mAb 11B11 reverses many of the isotype alterations in the transgenic mice, indicating that these changes arise as a direct consequence of IL-4 secretion.

Animals↗
PubMed1991

Histologic analysis of T lymphocyte activation in reactive lymph nodes.

As an approach to defining the anatomic sites of T cell activation in situ, we have developed an immunocytochemical stain for IL-2, a T cell-derived cytokine synthesized shortly after Ag-induced activation. Analysis of lymph nodes from mice immunized with keyhole limpet hemocyanin emulsified in CFA demonstrates that the IL2+ cells appear in a perivascular location 4 days after antigenic challenge. After germinal centers develop, IL-2+ cells are situated in a parafollicular pattern. Serial sections stained for different types of APC, including B cells, interdigitating dendritic cells, and macrophages, demonstrate a close physical association between IL-2+ cells and macrophages. These findings may have important implications for defining how APC bearing processed Ag and Ag-specific T cells interact in the complex environment of lymphoid tissues.

Animals↗
PubMed1991

Anergy in immature B lymphocytes. Differential responses to receptor-mediated stimulation and T helper cells.

We have compared the responses of purified neonatal and adult B lymphocytes to stimulation by anti-Ig antibodies, which are functional analogues of Ag, and by Th cells. Neonatal B cells are markedly deficient in proliferative responses to anti-Ig antibodies + IL-4 or to anti-Ig conjugated to dextran, both of which induce strong proliferation of adult B cells in the absence of T lymphocytes. Anti-Ig antibodies actually inhibit the functional responses of neonatal B cells, even to polyclonal stimuli such as LPS. However, Th cells induce both proliferation and Ig secretion by neonatal B cells in the presence of Ag that bind to B cell Ig and are subsequently presented by the B cells. Thus, in neonatal B lymphocytes, cross-linking of membrane Ig in the absence of Th cells has a net inhibitory effect, and this inhibition is overcome by T cell help. These results also suggest that unresponsiveness or tolerance to thymus-independent Ag is induced in the B cells themselves, but tolerance to thymus-dependent proteins resides primarily in the T cell compartment.

Aging↗
PubMed1991

Cytoplasmic tail deletion converts membrane immunoglobulin to a phosphatidylinositol-linked form lacking signaling and efficient antigen internalization functions.

Membrane-bound immunoglobulin (mIg) is the antigen receptor on B lymphocytes mediating early events in antigen presentation and signal transduction. Wild-type human mIgM constructs transfected into the murine B-cell lymphoma A20 are expressed as transmembrane proteins with antigen presentation and signaling functions comparable to the endogenous mIgG2A; the transfected wild-type mIgM is internalized rapidly after anti-Ig cross-linking. Transfected constructs lacking the normal three-amino acid cytoplasmic tail are expressed exclusively as phosphatidylinositol-linked proteins, lack both antigen presentation and signal transduction functions, and are internalized slowly following anti-Ig binding. The molecular mass of the cytoplasmic tail-deleted phosphatidylinositol-linked Ig molecule is consistent with cleavage of the transmembrane residues during processing. Cytoplasmic domains may therefore regulate the mode of expression of membrane proteins and thereby influence their functional capabilities.

Animals↗
PubMed1991

Activation of functionally distinct subsets of CD4+ T lymphocytes.

The studies summarized in this review have established that cloned lines of CD4+ T cells that produce distinct cytokines differ markedly in their responses to different forms of antigenic stimulation. Furthermore, we are beginning to develop experimental systems for better defining the signals that stimulate the differentiation of resting T cells into functionally distinct subsets. From these studies it is possible to construct the following hypothetical model for the differentiation of mature CD4+ T cells. Resting cells produce IL2 as the principal growth factor, IFN gamma, and little or no IL4. Antigenic stimulation in the presence of IL4 (which may be produced by non-T cells) leads to the preferential expansion of IL4-producing cells. These cells secrete their cytokines maximally when stimulated with antigens presented by B cells, which are also the principal targets of these cytokines. Continued expansion of IL4-producing T cells may require antigen exposures that also stimulate the production of IL1 by macrophages. In the absence of IL4 and IL1 (and in the presence of costimulators that are not yet defined) the T cells that are preferentially expanded belong to the IL2-producing subset. In addition, each subset may produce cytokines that stimulate the expansion of that subset and inhibit the other (Fiorentino et al., 1989). It is apparent that a number of assays and reagents need to be developed if these results are to be extended to physiologic immune responses. First, it is important to identify surface molecules that may serve as phenotypic markers for functionally distinct subsets of CD4+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

T-cell-mediated activation of B cells.

Antibody responses to protein antigens are dependent on helper T lymphocytes, which provide necessary growth and differentiation, inducing stimuli to antigen-specific B cells. Recent investigations have focused on the mechanisms of T-B interactions, and the nature of the T-cell-derived signals that are needed for activation and expansion of B cells.

Animals↗
PubMed1990

Heterogeneity of helper/inducer T lymphocytes. III. Responses of IL-2- and IL-4-producing (Th1 and Th2) clones to antigens presented by different accessory cells.

Murine CD4+ T cell clones have been classified into at least two subsets, Th1 and Th2, on the basis of their distinct lymphokine secretion profiles and functions. In the present study, we compared the functional responses of Th1 and Th2 clones to Ag presentation by splenic B cells and peritoneal macrophages. Th2 clones secreted IL-4 in response to Ag presented by resting B cells, but their optimal proliferation required the addition of IL-1 or a source of IL-1. The degree of IL-1 dependence varied among the four Th2 clones examined. In contrast, Th1 clones secreted IL-2 and proliferated in response to Ag presented by both B cells and macrophages, without any requirement for exogenous IL-1. Furthermore, the proliferation of Th2 clones in response to Ag presented by splenocytes or macrophages was inhibited by an IL-1R antagonist. These results indicate that IL-1 is an important costimulator for the expansion of the Th2 subset of CD4+ T cells. The different requirements for the proliferation of Th1 and Th2 cells may be responsible for the preferential expansion of one or the other subset under different conditions of immunization.

Animals↗
PubMed1990

Mutations of immunoglobulin transmembrane and cytoplasmic domains: effects on intracellular signaling and antigen presentation.

The membrane-bound form of immunoglobulin serves as an antigen-specific receptor for B cells mediating signal transduction and antigen presentation. We have developed an assay that reconstitutes both these physiologic responses with respect to the antigen phosphorylcholine. By introducing specific mutations in the human Ig mu chain gene, we have shown that certain transmembrane residues and the short cytoplasmic domain are crucial for these two activities. Moreover, elimination of a single transmembrane hydroxyl group severely inhibits antigen presentation without affecting signal transduction, suggesting that these two functions are mediated by different protein interactions.

Amino Acid Sequence↗
PubMed1990

IL-4 induces allergic-like inflammatory disease and alters T cell development in transgenic mice.

We have assessed the biologic role of IL-4 by fusing its gene to an immunoglobulin promoter/enhancer and introducing it into transgenic mice. By attenuating the transgene promoter through the insertion of E. coli lac operator sequences, we have created a series of animals that constitutively express varying amounts of IL-4. Overexpression of IL-4 results in a marked increase in serum IgE levels and the appearance of an inflammatory ocular lesion (blepharitis) with characteristic histopathologic features seen in allergic reactions. In addition, expression of the IL-4 transgene in the thymus perturbs T cell maturation, reducing the population of immature CD4+CD8+ thymocytes and peripheral T cells while increasing the population of mature CD8+ thymocytes. These results demonstrate that deregulation of a single cytokine gene in vivo can induce a complex inflammatory reaction resembling that observed in human allergic disease.

Animals↗
PubMed1990

Heterogeneity of helper/inducer T lymphocytes. IV. Stimulation of resting and activated B cells by Th1 and Th2 clones.

To test the hypothesis that resting and previously activated B lymphocytes differ in their proliferative and differentiative responses to various Th cell-derived stimuli, we have examined the interactions of purified small (resting) and large (activated) murine B cells with rabbit Ig-specific Th1 and Th2 clones in the presence of the Ag analogue, rabbit anti-mouse Ig antibody. Small numbers of Th2 cells induce strong Ag-dependent proliferation of and Ig secretion by both resting and activated B lymphocytes. In contrast, Th1 clones stimulate lower responses of activated B cells and fail to stimulate small resting B cells. An interaction with Th1 clones does make small B cells responsive to the Th2-derived cytokine, IL-4, indicating that Th1 clones are capable of delivering some but not all the stimuli necessary for the induction of humoral immunity. Finally, in order to compare the responses of small and large B cells to cognate interactions and secreted cytokines, we used an autoreactive I-Ak-specific Th2 line. This line induces proliferation of and Ig secretion by I-Ak expressing but not H-2d resting and activated B cells as a result of cognate interactions. However, when the H-2d B cells are bystanders in the presence of cytokine secretion by this Th2 line, or are directly exposed to Th2-derived cytokines, both small and large B cells are induced to proliferate but only the large B cells secrete antibody. These results indicate that the magnitude and nature of antibody responses depend on three principal factors: the cytokines produced by Th cells, the state of activation of the responding B lymphocytes, and whether the B cells are recipients of cognate help or are bystanders at the site of T cell stimulation. Our findings also confirm the view that cognate T-B interactions are most efficient for initiating B cell responses and may allow B cells to subsequently respond to a variety of T cell-derived cytokines.

Animals↗
PubMed1990

Anti-CD3 antibody induces unresponsiveness to IL-2 in Th1 clones but not in Th2 clones.

Culture of murine T cells with immobilized (platebound) anti-CD3 antibody results in autocrine growth factor secretion in both Th1 (IL-2 producing) and Th2 (IL-4 producing) cells. Using a panel of murine T cell clones, we demonstrate that the IL-2-induced proliferation of Th1 clones is dramatically inhibited by immobilized anti-CD3 antibody, whereas that of Th2 clones is not. This unresponsiveness of Th1 clones to IL-2 is not due to decreases in IL-2R expression. Supernatants from Th1 or Th2 cell cultures fail to alter the effects of anti-CD3 on the two types of clones, suggesting that unresponsiveness induced in Th1 clones or the lack thereof in Th2 clones is not mediated by a stable cytokine(s). Accessory cells enhance the proliferation of Th1 cells exposed to low concentrations of anti-CD3, but the unresponsiveness induced by high concentrations of anti-CD3 is not prevented by accessory cells. Finally, soluble anti-CD4 antibody prevents the induction of the unresponsive state even at high concentrations of anti-CD3. These experiments demonstrate that two subsets of cloned CD4+ T cells differ in their responses to anti-CD3, and that CD4 molecules may play a critical role in regulating the outcome of receptor-mediated stimulation.

Animals↗
PubMed1990

Patterns of cytokine secretion in murine leishmaniasis: correlation with disease progression or resolution.

Susceptibility or resistance to infection with Leishmania major correlates with the ability of mice to produce characteristic panels of lymphokines in response to the parasite. To investigate the role of antigen-presenting cells in this phenomenon, we developed a model system which used congenic (H-2d) susceptible and resistant mice. L. major-specific T cells were isolated from infected BALB/c and B10.D2 mice, and the cells were restimulated in vitro on syngenic or congenic antigen-presenting cells. BALB/c L. major-reactive T cells restimulated with either antigen-presenting cell produced high levels of interleukin-4 and low levels of gamma interferon. In contrast, T cells from B10.D2 mice produced gamma interferon. Radiation-induced chimeras reconstituted with BALB/c bone marrow also produced more interleukin-4 in response to L. major than did chimeras reconstituted with B10.D2 bone marrow. To test whether this pattern of cytokine secretion was unique to infection with L. major, we infected the mice with a second intracellular pathogen, Mycobacterium bovis BCG. Mycobacterium-specific T cells from both BALB/c and B10.D2 mice produced interleukin-2 and no interleukin-4. Finally, when BALB/c mice were vaccinated with avirulent L. major, the induced resistance correlated with reduced production of interleukin-4 but no increase in gamma interferon production. Instead, T cells from the vaccinated mice produced high levels of tumor necrosis factor. This suggests that tumor necrosis factor, in addition to gamma interferon, may be involved in resistance to L. major and that interleukin-4 may inhibit the leishmanicidal activity of tumor necrosis factor and/or gamma interferon.

Animals↗
PubMed1989

Immunodeficiency in graft-versus-host disease (GVHD). II. Effects of GVHD-induced suppressor cells on CD4+ T cell clones.

Lethally irradiated mice transplanted with H-2-matched, minor histocompatibility-disparate bone marrow develop graft-vs-host disease (GVHD) that is associated with severe immunodeficiency. Splenocytes from such mice contain radioresistant cells that profoundly suppress normal lymphocyte function. We now show that GVHD-induced suppressor cells also inhibit the proliferation of CD4+ T cell clones specific for different Ag and class II MHC determinants. These suppressors have a dominant anti-proliferative effect, because they inhibit DNA synthesis in response to receptor-mediated stimulation and growth-promoting lymphokines, without abolishing lymphokine secretion or lymphokine receptor expression by the cloned T cells. The implications of these findings, and the usefulness of T cell clones for studying immune suppression, are discussed.

Animals↗