Localization of human antigen-specific helper and suppressor function in distinct T-cell subpopulations

Heijnen, Cobi J.; Uytdehaag, Fons G. C. M.; Gmelig-Meyling, F.H.J.; Ballieux, R. E.

doi:10.1016/0008-8749(79)90173-4

Cited by 79 publications

(26 citation statements)

References 23 publications

(22 reference statements)

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“…The previous studies on antigen-induced T cell help in the human system have been "conflicting," with some investigators noting radiation sensitivity and others noting a radiation resistance to antigen-induced T cell help (10,25). The data present in this study using an antigen-specific system have confirmed the earlier observations on the effect of irradiation on PWM-induced T cell help and have provided evidence that the T cell involved in antigen-induced, antigen-specific antibody production is, in contrast to some earlier reports (8,10,25), exquisitely sensitive to radiation. Irradiation can have a number of effects on the expression of cellular function.…”

Section: Discussionsupporting

confidence: 51%

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Antigen-induced human T cell help. Precursor frequency, radiation sensitivity, and allogeneic effects.

Lane¹,

Whalen²,

Fauci³

1983

J. Clin. Invest.

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A B S T R A C T We have recently noted marked differences between the in vitro responses of human B lymphocytes to stimulation with soluble antigens vs. stimulation with mitogens. In the present study, these differences were analyzed in terms of the precursor frequencies for the T cells and B cells involved and in terms of the radiation sensitivity of the T cells providing help in the two systems. Marked differences were found between antigen-induced and mitogen-induced systems with regard to T cell precursor frequencies and radiation sensitivity. In contrast, the precursor frequencies for the B cells involved in the two systems were approximately the same. In addition, having developed a system for the study of human antigen-specific B cell responses, we were interested in delineating the nature of the allogeneic effects that might be operative in this system. Marked allogeneic effects, both positive and negative, were noted in this system and will need to be taken into account in any studies that try to address the question of the genetic restriction, if any, that exists in human antigen-specific T cell-B cell collaboration.Appreciation of the marked differences between the antigen-specific and mitogen-induced activation and immunoregulation of human B cell responses will be of importance in understanding the relationship between specificity and nonspecificity of antibody production in normal and disease states. INTRODUCTIONT cell regulation of B cell reactivity is an area of major interest and importance in both animal and human systems. With the recent availability of several systems Address all correspondence to Dr. H. Clifford Lane. Received for publication 20 January 1983 and in revised form 30 March 1983. to study human B cell function in vitro, considerable interest has centered around the precise nature of the T cell regulation of human B cell responses in both polyclonal and antigen-specific assay systems. Unfortunately, there have been conflicting data among sev-. eral of these systems (1-10). Of particular note has been the divergence of results with regard to the radiosensitivity of T cell help and the relative contributions of allogeneic effects in the mitogen-induced vs. antigen-induced human B cell systems. Disagreement with regard to this latter point has led to difficulty in delineating the precise nature of genetic restrictions in T cell-B cell collaboration in antigen-specific responses as well in appreciating the scope of allogeneic effects in co-culture experiments now commonly used in the study of patients with immunemediated or immunodeficiency diseases.Recently, in vitro systems have been developed for the study of antigen-induced, antigen-specific antibody production and secretion into culture supernatants by human B cells (11)(12)(13)(14). The use of enzymelinked immunosorbent assays (ELISA)l has proven to be extremely useful in these studies because of their simplicity, sensitivity, and specificity. These advances have allowed for a more precise study of the mechanisms involved in...

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Section: Discussionsupporting

confidence: 51%

“…Unfortunately, there have been conflicting data among sev-. eral of these systems (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Of particular note has been the divergence of results with regard to the radiosensitivity of T cell help and the relative contributions of allogeneic effects in the mitogen-induced vs. antigen-induced human B cell systems.…”

Section: Introductionmentioning

confidence: 99%

Antigen-induced human T cell help. Precursor frequency, radiation sensitivity, and allogeneic effects.

Lane¹,

Whalen²,

Fauci³

1983

J. Clin. Invest.

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“…Human PBMCs were prepared by Ficoll-Hypaque gradient centrifugation from healthy blood donors, and T lymphocytes were isolated by rosetting with 2-amino-ethylisothiuronium-treated sheep red blood cells (Heijnen et al, 1979). T lymphocytes were cultured overnight in culture medium (RPMI 1640 supplemented with 10% fetal bovine serum, 2 mM glutamine, and antibiotics) to remove erythrocyte ghosts.…”

Section: Methodsmentioning

confidence: 99%

Oxidative Stress Decreases G Protein-Coupled Receptor Kinase 2 in Lymphocytes via a Calpain-Dependent Mechanism

et al. 2002

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G protein-coupled receptor kinase (GRK) 2 plays a crucial role in regulating the extent of desensitization and resensitization of G protein-coupled receptors (GPCRs). We have shown that the expression level of GRK2 in lymphocytes decreases during inflammatory diseases such as arthritis. Reactive oxygen species play an important role in a variety of inflammatory conditions, including arthritis. We demonstrate herein that oxidative stress, induced by exposure of lymphocytes to H 2 O 2 , results in a 50% reduction in GRK2 protein levels and GRK activity with no changes in mRNA expression. Treatment of lymphocytes with the tyrosine kinase inhibitor genistein partially reverses the effect of H 2 O 2 on GRK2 levels, although we did not detect direct tyrosine phosphorylation of GRK2. Inhibition of the nonproteasomal protease calpain by calpeptin can prevent the H 2 O 2 -induced GRK2 decrease. In vitro experiments confirm that GRK2 is partially digested by m-calpain in a calciumdependent way. Functionally, H 2 O 2 -induced decrease in GRK2 levels is associated with an ϳ70% decrease in agonist-induced ␤ 2 -adrenergic receptor sequestration. We describe oxidative stress as a novel mechanism for regulation of the intracellular level of GRK2 during inflammatory processes. Moreover, our data demonstrate that oxidative stress may change the functioning of GPCRs via calpain-dependent regulation of GRK2 levels.

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“…It has been reported that T cell factors of murine origin can be absorbed on human PBL of certain donors (27) and, vice versa, human T cell factors were shown to activate murine B cells for antibody production (21,28). Heijnen and coworkers (29,30) have demonstrated collaboration between human helper T cell factors and human B cells; however, they worked with antigenic systems to which the response is not genetically controlled and all individuals were expected to respond to them.…”

mentioning

confidence: 99%

Immune response potential to poly(Tyr,Glu)-poly(DLAla)--poly(Lys) of human T cells of different donors.

Katz¹,

Bentwich²,

Eshhar³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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Human peripheral blood T cells ofnormal donors were activated in vitro with autologous adherent cells pulsed with poly(LTyr,LGlu)-poly(DLAla)--poly(LLys) [abbreviated (T,G)-A--L]. The "educated" T cells were tested: (i) for their ability to produce a (T,G)-A--L-specific T cell-replacing factor in the cooperation with B cells for antibody responses in vivo or in vitro and (ii) for their ability to proliferate in the presence of a second stimulus of(T,G)-A--L. Results ofscreening of66 donors demonstrated that educated T cells ofabout 50% ofthe donors produced an active (T,G)-A--L-specific factor, whereas activated cells of only half of the factor producers were capable of proliferating in the presence of the antigen. Thus, as reported for all other species studied, human individuals differ in their response potential to (TG)-A--L.Immune response (Ir) genes have been found in a variety of species (1-4) and therefore it is widely assumed that they must exist in humans. For the majority of antigenic systems studied, Ir genes were found to be linked to the major histocompatibility complex (MHC) ofthe species (1, 2, 5-8). Hence, it is likely that Ir genes in the human will map close to the HLA-D locus because of its similarity to the I region of the mouse (9). The Ir genes also appear to be the obvious candidates to explain involvement ofthe MHC in disease (10). In spite ofthe paramount importance of understanding the function of putative Ir genes in humans, the existence ofsuch genes has not been established yet, probably due to the complexity ofthe antigenic systems that play a role in disease occurrence (10, 11) and due to the ethical constraints on immunizing humans with antigens.One of the antigenic systems most extensively used for studies on the genetic regulation of immune responsiveness in a variety of species is that of the synthetic polypeptide antigen poly(LTyr,LGlu)-poly(DLAla)--poly(Lys), abbreviated as (T,G)-A--L (1, 2, 5, 12, 13). In the mouse, antibody responses (2, 5), delayed-type hypersensitivity (DTH) reactions (14), and antigen-dependent proliferation responses (15) specific to (T,G)-A--L were all found to be genetically controlled. In addition, an antigen-specific T cell-replacing factor that could cooperate with B cells for the production of(T, G)-A--L-specific antibodies has been reported for this synthetic polypeptide (16,17). One of the properties of antigen-specific T cell-replacing factors is their ability to interact with B cells across major histocompatibility (H-2) "barriers" (16, 17), although their production is regulated by Ir genes (16, 18) and they possess Ia determinants (17,19). Furthermore, it has been shown that these factors are not species specific (20,21). It appeared, therefore, that the (T,G)-A--L antigenic system is most adequate for attempts to study genetically controlled immune responses in humans.In the present study we have generated in vitro "educated"human peripheral blood leukocytes (PBL) of normal donors to (T,G)-A--L. The educated cells were tested for t...

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Localization of human antigen-specific helper and suppressor function in distinct T-cell subpopulations

Cited by 79 publications

References 23 publications

Antigen-induced human T cell help. Precursor frequency, radiation sensitivity, and allogeneic effects.

Antigen-induced human T cell help. Precursor frequency, radiation sensitivity, and allogeneic effects.

Oxidative Stress Decreases G Protein-Coupled Receptor Kinase 2 in Lymphocytes via a Calpain-Dependent Mechanism

Immune response potential to poly(Tyr,Glu)-poly(DLAla)--poly(Lys) of human T cells of different donors.

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