T Cells with Two Tcrβ Chains and Reactivity to both MHC/Idiotypic Peptide and Superantigen

Munthe, Ludvig A.; Blichfeldt, Erik; Sollien, Anders; Dembić, Zlatko; Bogen, Bjarne

doi:10.1006/cimm.1996.0162

Cited by 18 publications

(21 citation statements)

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“…1 The different T lymphocyte effector responses that can be elicited, ie quality and magnitude of the response, depend on the density of the T lymphocyte receptors as well as on target cell density. [10][11][12][13][14] A detailed understanding of antigen-receptor/antigen relationships is important for the efficient generation and expansion of optimally reactive, tumor-specific CTLs for immunotherapy, since adoptive transfer of tumor-specific CTLs has shown significant clinical benefit. 15,18 However, tumor-specific CTLs are difficult to isolate from cancer patients and their expansion to therapeutic numbers is time-consuming and the succes rate unpredictable.…”

Section: Discussionmentioning

confidence: 99%

“…14,30 The few reports available in the literature on the functional balance between TCR density and T lymphocyte response to antigens show that a decrease in TCR density results in reduced T lymphocyte responses. 11,13 Hence, quality and quantity of T lymphocyte responses depend on and differ in (1) required thresholds of TCR occupancies; (2) antigen densities; and (3) antigen potencies. Different T lymphocyte responses may require…”

Section: Discussionmentioning

confidence: 99%

“…Chimeric receptor and TAA densities also co-determine levels of T lymphocyte IFN-␥ and TNF-␣ production Individual CTLs can exercise distinct biological responses as a function of percentage of TCR occupancy, 8,[10][11][12][13][14] which in turn is determined by ligand density and potency. 12 Therefore we studied the capacity of chRec LOW and HIGH POS T lymphocytes to secrete INF-␥ and TNF-␣ in response to G250 TAA LOW and HIGH POS RCCs.…”

Section: Kinetics Of Tumor Cell Lysis Do Not Depend On Chimeric Recepmentioning

confidence: 99%

“…[11][12][13][14]31 During the preparation of this manuscript we became aware of the data recently published by Alvarez and Russell, 32 who used a model system using Jurkat T cells with tetracycline-regulatable ch-Rec densities to study their level of IL-2 response as a function of plastic-coated antigen density. They concluded that Jurkat T cells can be engineered to discriminate…”

Section: Figure 4 Ch-rec High-pos Ctls Can Lyse Taa Low-pos Tumor Celmentioning

confidence: 99%

“…8,[10][11][12][13] The limited data that are available on the effect of low versus high TCR densities on antigen reactive T lymphocyte responses show a correlation with T lymphocyte activities. 11,13,14 A detailed understanding of the functional balance between TCR and TAA densities is therefore essential for the generation of optimally antitumor reactive T lymphocytes for cancer gene-immunotherapy now that adoptive transfer of tumor-specific CTLs to patients has demonstrated clinical benefit. However, specific CTLs from patients are difficult to isolate and cumbersome to expand to therapeutic numbers and this critically limits their clinical application.…”

Section: Introductionmentioning

confidence: 99%

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Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

2000

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Genetically engineered expression of tumor-specific single chain antibody chimeric receptors (ch-Rec) on human T lymphocytes endow these cells with the parental monoclonal antibody (mAb) dictated tumor specificity and may be useful for clinical immuno-genetherapy. Therefore it was of importance to assess how the densities of tumor-specific receptors and tumor associated antigens (TAA), respectively, affect primary human T lymphocyte functions in relation to target cell susceptibilities to lysis. We therefore studied the functional balance between ch-Rec densities on human T lymphocytes and TAA on tumor cells. The gene construct encoding a ch-Rec derived from (1) a renal carcinoma cell (RCC) specific mouse mAb (G250), and (2) the human signal transducing Fc(⑀)RI ␥-chain was used. To obtain chRec HIGH-POS and ch-Rec LOW-POS T lymphocytes, two distinct retroviral vectors were used to introduce the gene constructs into primary human T lymphocytes. Levels of ch-Rec-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Kinetics Of Tumor Cell Lysis Do Not Depend On Chimeric Recepmentioning

confidence: 99%

Section: Figure 4 Ch-rec High-pos Ctls Can Lyse Taa Low-pos Tumor Celmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

2000

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Resting small B cells present endogenous immunoglobulin variable-region determinants to idiotope-specific CD4+ T cellsin vivo

1999

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Antigenic determinants localized within the highly diversified V‐regions of Ig are called idiotopes (Id). Processed Id‐peptides can be presented on MHC class II molecules to CD4+ T cells. If B cells present their endogenous Id‐peptides, T cell activation could occur in the absence of nominal antigen, a potentially important process in T‐B cooperation and immune regulation. To test this idea, we used mice made transgenic for a λ2 L‐chain (Id+ mice). Another transgenic mouse strain expresses TCR transgenes with specificity for the Id (λ2), presented on MHC class II molecules. When highly purified sorted Id+ B cells and Id‐specific T cells were sequentially injected into MHC syngeneic SCID host, T cell became blastoid, CD69+ and proliferated. To exclude any role of host APC, MHC incompatible Rag2– / – mice (H‐2b) were used as recipients for the Id+ B and Id‐specific T cells, with similar results. Exposure to extracellular Id+ immunoglobulin (Ig) was not sufficient for Id priming of B cells in vivo, highlighting the preferential presentation of Id peptides derived from endogenous Ig, by B cells. The results suggest that B cells presenting Id self‐peptides generated by V(D)J recombinations or somatic mutations may directly stimulate T cell in vivo in the absence of conventional antigen.

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Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4⁺ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma

Bogen

1996

Eur J Immunol

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146

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Tumors could escape an immune attack by inducing peripheral T cell tolerance. To test this, T cell receptor (TCR)-transgenic mice were injected with plasmacytoma cells secreting a highly tumor-specific antigen, a monoclonal immunoglobulin (Ig), for which the transgene-encoded TCR is specific. The TCR recognizes a third hypervariable region idiotypic (Id) peptide of the Ig, presented by a class II molecule on host antigen-presenting cells. The TCR-transgenic mice have previously been shown to be protected against an Id+ plasmacytoma challenge. In the present experiments, the protection was deliberately overwhelmed by subcutaneous injection of large numbers of plasmacytoma cells. Such tumor mice, chronically exposed to increasing amounts of monoclonal Ig, delete Id-specific CD4+ T cells in their peripheral lymphoid organs and in the tumor. The residual CD4+ cells express endogenous, rather than transgene-encoded TCR alpha chains. Peripheral deletion, functional T cells unresponsiveness, and thymocyte deletion are all first detected at the same serum concentration of monoclonal Ig, approximately 50 micrograms/ml (0.3 microM), and become more and more profound as the tumor burden increases. The results suggest that peripheral T cell tolerance to Id could be a tumor escape mechanism in patients with B cell malignancies. In addition, the findings have implications for T cell tolerance to Ig V regions in normal individuals.

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T Cells with Two Tcrβ Chains and Reactivity to both MHC/Idiotypic Peptide and Superantigen

Cited by 18 publications

References 0 publications

Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

Resting small B cells present endogenous immunoglobulin variable-region determinants to idiotope-specific CD4+ T cellsin vivo

Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4⁺ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma

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T Cells with Two Tcrβ Chains and Reactivity to both MHC/Idiotypic Peptide and Superantigen

Cited by 18 publications

References 0 publications

Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

Functional balance between T cell chimeric receptor density and tumor associated antigen density: CTL mediated cytolysis and lymphokine production

Resting small B cells present endogenous immunoglobulin variable-region determinants to idiotope-specific CD4+ T cellsin vivo

Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4+ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma

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Product

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Peripheral T cell tolerance as a tumor escape mechanism: deletion of CD4⁺ T cells specific for a monoclonal immunoglobulin idiotype secreted by a plasmacytoma