Self peptide requirement for class II major histocompatibility complex allorecognition.

Demotz, Stéphane; Sette, Alessandro; Sakaguchi, Kazuyasu; Buchner, R; Appella, Ettore; Grey, Howard M.

doi:10.1073/pnas.88.19.8730

Cited by 25 publications

(24 citation statements)

References 22 publications

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“…ICS for IFN-␥-producing antigen-specific CD4 ϩ T cells was performed as previously described (6,31,32) with modifications. PBMC (2 million/ml) were incubated with HIV-1 MN gp160 (final concentration, 5 g/ml) or peptide (final concentration, 2 g/ml) in the presence of anti-CD49d (Beckman Coulter, Miami, Fla.) and anti-CD28 (BD Biosciences, San Jose, Calif.) purified MAbs (final concentration, 1.0 g/ml) at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Peptide-binding assays were performed as described previously (6,30,31). Specifically, purified human HLA class II molecules (5 to 500 nM) were incubated with various unlabeled peptide inhibitors and 1 to 10 nM 125 I-radiolabeled probe peptide for 48 h in phosphate-buffered saline containing 0.05% Nonidet P-40 in the presence of a protease inhibitor cocktail.…”

Section: Methodsmentioning

confidence: 99%

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Early Induction and Maintenance of Env-Specific T-Helper Cells following Human Immunodeficiency Virus Type 1 Infection

Malhotra

Holte²,

Zhu

et al. 2003

J Virol

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Mounting evidence points to a role for CD4؉ T-helper (Th) cell activities in controlling human immunodeficiency virus type 1 (HIV-1) infection. To determine the induction and evolution of Th responses following acute infection, we prospectively analyzed Env-and Gag-specific Th responses longitudinally for 92 patients with acute (n ‫؍‬ 28) or early (n ‫؍‬ 64) HIV-1 infection (median, 55 days postinfection [DPI]). The probability of detecting HIV-1-specific lymphoproliferative responses was remarkably low, and when present, the responses were more likely to be Gag specific than Env specific (16 versus 5%). Env-specific responses were significantly more common in patients presenting at <30 DPI than in those presenting at 30 to 365 DPI (21 versus 0.5%, P ‫؍‬ 0.001). By contrast, Gag-specific responses occurred with similar frequencies among subjects presenting at <30 DPI and 30 to 365 DPI (13 versus 17%, P ‫؍‬ 0.6). After treatment, and regardless of the duration of infection before therapy, Gag-specific Th responses predominated. Furthermore, some acutely infected subjects lost detectable Env-specific Th proliferative responses, which failed to reemerge upon treatment. Detailed analysis for one such subject revealed Env-specific lymphoproliferation at 11 DPI but no detectable Env-specific lymphoproliferation or ex vivo gamma interferon (IFN-␥) secretion at multiple subsequent time points. Env-specific CD4 ؉ T-cell clones from 11 DPI recognized six epitopes in both conserved and variable regions within gp120 and gp41, exhibited major histocompatibility complex-restricted cytotoxicity, and secreted high levels of antiviral cytokines. T-cell receptor clonal transcript analyses and autologous virus sequencing revealed that Th cells induced during acute infection were maintained and there were no Th escape mutations. Subsequent analysis for this subject and six of seven others revealed detectable IFN-␥-secreting cells, but only following in vitro gp160 stimulation. In summary, we conclude that Env-specific Th responses are elicited very early in acute infection and may precede Gag-specific responses. The inability to detect Env-specific Th responses over time and despite antiretroviral therapy may reflect low frequencies and impaired proliferative capacity, and viral escape is not necessary for this to occur.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Early Induction and Maintenance of Env-Specific T-Helper Cells following Human Immunodeficiency Virus Type 1 Infection

Malhotra

Holte²,

Zhu

et al. 2003

J Virol

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“…Class II molecules were purified by affinity chromatography, essentially as described previously (20), using the mAb LB3.1 coupled to Sepharose CL-4B beads. Lysates were filtered twice through two precolumns of inactivated Sepharose CL-4B and protein A-Sepharose, and then passed over the anti-DR column.…”

Section: Methodsmentioning

confidence: 99%

“…Two patients discontinued the study at 32 and 40 weeks, thus extended follow-up for these patients is not available. The mean age of the study participants was 31 years (range [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38], and 95% of the patients experienced a symptomatic illness during acute infection. The median duration of infection at study entry was 43 days (range 9-137).…”

Section: Study Populationmentioning

confidence: 99%

Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment

Malhotra¹,

Holte²,

Dutta³

et al. 2001

J. Clin. Invest.

112

110

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“…Most recently, McConnell and coworkers (7) have succeeded in showing, by energy-transfer studies, that two full-length peptides fit into one binding groove, provided that the class II molecule is in its floppy conformation. These findings have interesting implications for alloreactive T-helper cells that are thought to recognize endogenously synthesized cellular peptides associated with an allogeneic MHC (8) or an allo-MHC whose binding site is unoccupied (9). Since there is growing evidence that MHC-derived peptides are also presented to T-helper cells (10)(11)(12), certain combinations of cobinding self-and allopeptides may mimick allo-MHC determinants that are relevant for allorecognition.…”

mentioning

confidence: 99%

Evidence for cobinding of self- and allopeptides to human class II major histocompatibility antigen DR1 by energy transfer.

Kropshofer

Max

Kalbacher

1993

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

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Purified human class II major histocompatibility antigen HLA-DR1 was subjected to high-performance gel filtration with fluorescence detection to investigate simultaneous binding of two classes of peptides: the N-terminally fluoresceinated allopeptides fluorescein isothiocyanate (FITC)-conjugated and , derived from the third hypervariable region of the I8 chain of DR1 and DR3, respectively, and the DR1-associated selfpeptide SP3, carrying the fluorophor 7-amino-4-methylcoumarin-3-acetic acid (AMCA) at the N terminus. By analyzing the dimer-associated fluorescence signals, we measured an interpeptide energy transfer AMCA -FITC that proved to be peptide-specific: it did not occur after replacement of the allopeptide by the DR1-restricted peptide IM-(18-29) from influenza matrix protein, whereas it was restored by SP3, due to the high homology of SP3 and allopeptide. Transfer analyses with truncated AMCA-SP3 and AMCA-IM-(18-29) are consistent with Leu-3 being a common anchor residue of both peptides that allows an interaction with the hydrophobic specifity pocket around Ala-37 of the a, domain. This interaction is mirrored by the intrinsic fluorescence of neighboring Trp-43: we found the protein-peptide transfer Trp(DR1) -+ AMCA with AMCA-SP3 but with none of the allopeptides. Since each energy transfer affords close proximity of two fluorophors, the following picture emerges: self-or foreign peptides bind to the DR1 binding cleft by occupation of previously described specificity pockets. Simultaneously, allopeptides of the third hypervariable region or homologous peptides may occupy a cryptic binding site by displacing the p81-helix that normally lines the binding groove. Thus, the described complexes raise additional possibilities for the molecular basis of auto-or alloreactivity.Major histocompatibility complex (MHC) class II antigens are polymorphic peptide receptors that are loaded with peptides in post-Golgi compartments of an antigen-presenting cell (1). The resulting class II MHC-peptide complexes are of great immunological relevance, since their appearance on the surface of an antigen-presenting cell leads to up-or down-regulation of certain CD4+ T-helper cells that are crucial for self-nonself discrimination (2, 3). Class II molecules bear a single peptide-binding site deduced from sequence homologies and far-reaching functional analogies with crystallographically analyzed human class I antigens (4). Thereafter, both subunits contribute four N-terminal strands of a P-pleated sheet and a laterally overlying a-helical structure forming one-half of the proposed binding groove, respectively (5). The tertiary structure of these domains seems to be highly dependent on the existence of an appropriate peptide, as shown with mouse class II molecules (6): intact MHC-self-peptide complexes migrate as compact conformers (52-56 kDa), whereas heat or acid release of peptides results in slowly migrating floppy conformers (62-67 kDa) in SDS gels. Most recently, McConnell and coworkers (7) have succeeded in showin...

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Self peptide requirement for class II major histocompatibility complex allorecognition.

Cited by 25 publications

References 22 publications

Early Induction and Maintenance of Env-Specific T-Helper Cells following Human Immunodeficiency Virus Type 1 Infection

Early Induction and Maintenance of Env-Specific T-Helper Cells following Human Immunodeficiency Virus Type 1 Infection

Role for HLA class II molecules in HIV-1 suppression and cellular immunity following antiretroviral treatment

Evidence for cobinding of self- and allopeptides to human class II major histocompatibility antigen DR1 by energy transfer.

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