Beta 2-microglobulin is not required for cell surface expression of the murine class I histocompatibility antigen H-2Db or of a truncated H-2Db.

Allen, Hamish; Fraser, John D.; Flyer, David C.; Calvin, S; Flavell, Richard A.

doi:10.1073/pnas.83.19.7447

Cited by 196 publications

(148 citation statements)

References 36 publications

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“…In peptide-pulsing experiments, 10 ~' RMA-S cells, which were previously cultured overnight at 29~ in RPMI plus 10% FCS, were incubated with various concentrations of peptide at 29~ for 30 min. These cells were then transferred to a 37~ incubator for 3 h, after which the cells were washed and stained with anti-H-2D b mAb from tissue culture supernatant (B22.249) (31,32) and then FITC-conjugated rat antimouse Ig (Sigma Chemical Co.). RMA-S cells were incubated with LCMV nucleoprotein 118-127 (H-2 d restricted) (33) to determine background H-2D b expression.…”

Section: Methodsmentioning

confidence: 99%

Mature T cell reactivity altered by peptide agonist that induces positive selection.

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Kündig

Thomson

et al. 1996

The Journal of Experimental Medicine

144

100

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SummaryRecent studies have investigated how defined peptides influence T cell development. Using a T cell receptor-transgenic [32-microglobulin--deficient model, we have examined T cell maturation in fetal thymic organ cultures in the presence of various peptides containing single-alanine substitutions of the strong peptide agonist, p33. Cocultivation with the peptide A4Y, which contains an altered T cell contact residue, resulted in efficient positive selection. Several in vitro assays demonstrated that A4Y was a moderate agonist relative to p33. Although A4Y promoted positive selection over a wide concentration range, high doses of this peptide could not induce clonal deletion. Thymocytes maturing in the presence of A4Y were no longer able to respond to A4Y, but could proliferate against p33. These studies demonstrate that (a) peptides that induce eflficient positive selection at high concentrations are not exclusively antagonists; (b) some agonists do not promote clonal deletion; (c) positive selection requires a unique T cell receptor-peptide-major histocompatibility complex interaction; and (d) interactions with selecting peptides during T cell ontogeny may define the functional reactivity of mature T cells. T CRs expressed on maturing thymocytes interact withpeptide-MHC complexes on thymic stromal cells and transmit signals that lead to either positive or negative T cell selection (1-3). Positive selection is an active process that rescues self-MHC-restricted thymocytes from programmed cell death. In contrast, negative selection tolerizes potentially autoreactive T cells, either through clonal deletion or unresponsiveness. Clonal deletion physically removes thymocytes by inducing apoptosis, as compared with unresponsiveness, which modifies developing T cells so that they can no longer respond against the tolerizing antigen. Since positive and negative selection shape the TCR repertoire and define the basis of self-/non-self-antigens, much research has focused on understanding T cell development. Studies have addressed how clonotypic TCRs expressed on CD4+CD8 + double-positive thymocytes can distinguish between these two selection events. Although it has been demonstrated that peptides are involved in positive and negative selection (4, 5), it remains controversial whether the selecting ligand has a qualitative or quantitative role in determining the fate of the developing T cell.Recently, altered peptide ligands have been identified that can inhibit some or all mature T cell effector functions (6-10). Antagonist peptides are defined as ligands that engage TCRs and actively inhibit biological responses. Partial agonists are closely related peptides that stimulate a subset ofT cell effector functions (11). This is in contrast with agonist peptides, which induce a complete range ofT cell responses. Studies by Hogquist et al. (12,13) and Jameson et al. (14) showed a correlation between peptide antagonists and positive selection. These results suggest that a positively selecting peptide is qualitatively diffe...

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Section: Methodsmentioning

confidence: 99%

Mature T cell reactivity altered by peptide agonist that induces positive selection.

Sebzda

Kündig

Thomson

et al. 1996

The Journal of Experimental Medicine

144

100

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“…We were puzzled by the stability of the Cw7-free heavy chains and wondered whether they were all bound for disposal, or, similar to HLA-Cw1 and certain murine class I molecules (Potter et al, 1984;Allen et al, 1986;Smith et al, 1993;Machold et al, 1995), at least a fraction of HLA-Cw7 molecules could be expressed on the cell surface in the absence of β 2 m.…”

Section: Pulse-chase Analysis Of Fo-1 Melanoma Cellsmentioning

confidence: 99%

“…These heavy chains, 'free' of β 2 m, have been demonstrated to be either 'unfolded' (Allen et al, 1986;Smith et al, 1993), or at least partially folded (Machold et al, 1995), and to bear mature carbohydrates (Hansen et al, 1988;Machold et al, 1995). Biochemical and functional data in β 2 m knockout mice are consistent with the idea that both D b -and L d -free heavy chains may retain some ability to bind (Smith et al, 1993) and present (Lehmann-Grube et al, 1994;Cook et al, 1995) antigen even when synthesized in the absence of β 2 m. In contrast, there is no evidence that any of the more than 300 sequenced HLA-A and -B alleles might be constitutively expressed on the cell surface of most (Fellous et al, 1977;D'Urso et al, 1992;Gattoni-Celli et al, 1992;Wang et al, 1993;Bicknell et al, 1994;Porgador et al, 1997) β 2 m-defective cells of human origin.…”

mentioning

confidence: 99%

“…More recently, however, using antibodies capable of discriminating different conformations of class I molecules, several murine class I heavy chains, including D b , L d and K b molecules, have been detected at low levels on the surface of normal as well as transformed cells lacking the β 2 m subunit and/or the TAP complex (Potter et al, 1984;Allen et al, 1986;Smith et al, 1993;Machold et al, 1995). These heavy chains, 'free' of β 2 m, have been demonstrated to be either 'unfolded' (Allen et al, 1986;Smith et al, 1993), or at least partially folded (Machold et al, 1995), and to bear mature carbohydrates (Hansen et al, 1988;Machold et al, 1995).…”

mentioning

confidence: 99%

“…However, the efficiency of the retention and degradation mechanisms has been found to be different in different class I molecules. For instance, murine H2-D b (Allen et al, 1986), -L d (Smith et al, 1993) and human HLA-C (Neefjes and Ploegh, 1988) It has been proposed that clones of neoplastic cells unable to express one or more class I alleles might arise and be selected in vivo, in the immunocompetent host, possibly because they are provided with a distinctive ability to evade the immune surveillance (Garrido et al, 1993). Thus, the biochemical characterization of the various class I molecules in class I-defective cells bears implications on the mechanisms by which the various immune effectors control neoplastic cell growth.…”

mentioning

confidence: 99%

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Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the expression of HLA-A, -B, -C molecules

et al. 1999

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Summary Recent investigations have shown that malignant transformation may down-regulate the expression of class I HLA molecules, β 2 -microglobulin (β 2 m) and members of the antigen-processing machinery. In the present study, we HLA-genotyped and identified at a biochemical level the three (HLA-A25, -B8, -Cw7) class I alleles expressed by the previously described [D'Urso CM et al (1992) J Clin Invest 87: 284-292] β 2 m-defective human melanoma FO-1 cell line and tested their ability to interact with calnexin, calreticulin and the TAP (transporter associated with antigen processing) complex. All these alleles were found to bind calnexin, but not calreticulin or the poorly expressed TAP complex, both in parental and β 2 m-transfected FO-1 cells, demonstrating a complex defect of class I expression in FO-1 cells. In these conditions, Cw7 heavy chains interacted with calnexin more strongly than A25 and B8, and preferentially accumulated in the endoplasmic reticulum, in both a calnexin-associated and a calnexin-free form. In addition, they could be transported to the cell surface at low levels even in the absence of β 2 m, without undergoing terminal glycosylation. These results establish a parallel between HLA-C and the murine D b and L d molecules which have been found to be surface expressed and functional in β 2 m-defective cells. They also demonstrate distinctive features of HLA-C molecules. We propose that the accumulation of several assembly intermediates of HLA-C might favour the binding of peptide antigens not readily bound by HLA-A and -B molecules in neoplastic cells with suboptimal class I expression.

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Induction and functional characterization of β 2-microglobulin (β2-μ)-free HLA class I heavy chains expressed by β2-μ-deficient human FO-1 melanoma cells

et al. 1998

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The frequent loss of beta2-microglobulin (beta2-mu) in malignant cells has stimulated interest in the functional characteristics of beta2-mu-free HLA class I heavy chains, since this information contributes to assess the impact of beta2-mu abnormalities on the interaction of malignant cells with immune cells. Therefore, the present study has investigated the ability of beta2-mu-free HLA class I heavy chains to modulate NK cell-mediated lysis of melanoma cells and to present melanoma-associated antigen (MAA)-derived peptides to HLA class I-restricted, MAA-specific cytotoxic T lymphocytes (CTL). Beta2-mu-free HLA class I heavy chains were induced on beta2m null FO-1 cells by sequential incubation with IFN-alpha for 48 h at 37 degrees C and for 24 h at 26 degrees C. Transfection of cells with a wild-type H-2Ld gene (FO-1Ld) enhanced the induction of beta2-mu-free HLA class I heavy chains under such experimental conditions. Beta2-mu-free HLA class I heavy chains expressed on the cell membrane did not protect the B2m null FO-1 cells from NK cell-mediated lysis. Furthermore, FO-1 cells which express beta2-mu-free HLA-A2 heavy chains following transfection with a wild-type HLA-A2 gene were not lysed by HLA-A2-restricted, MAA-specific CTL lines and clones. These results indicate that association with beta2-mu is required for interaction of HLA class I molecules with NK inhibitory receptors and for peptide presentation to CTL.

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Beta 2-microglobulin is not required for cell surface expression of the murine class I histocompatibility antigen H-2Db or of a truncated H-2Db.

Cited by 196 publications

References 36 publications

Mature T cell reactivity altered by peptide agonist that induces positive selection.

Mature T cell reactivity altered by peptide agonist that induces positive selection.

Biosynthesis of HLA-C heavy chains in melanoma cells with multiple defects in the expression of HLA-A, -B, -C molecules

Induction and functional characterization of β 2-microglobulin (β2-μ)-free HLA class I heavy chains expressed by β2-μ-deficient human FO-1 melanoma cells

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