Developmentally Regulated Glycosylation of the CD8αβ Coreceptor Stalk Modulates Ligand Binding

Moody, Anne Marie; Chui, Daniel; Reche, Pedro A.; Priatel, John J.; Marth, Jamey D.; Reinherz, Ellis L.

doi:10.1016/s0092-8674(01)00577-3

Cited by 192 publications

(217 citation statements)

References 54 publications

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“…Different patterns of sialylation were found in different thymocyte subsets as well as the expression of sialyl transferases (1,2,35). Peanut agglutinin-binding properties vary from cortical to medullary thymocytes in association with sialic acid acquisition on the cell surface (1).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, an exogenous ␣2-3 sialyltransferase-like activity mediated by TS and working at the thymocyte vicinity may modify the cell surface, mimicking the endogenous expression of the equivalent enzyme, although in the wrong place and͞or at the wrong time. Exogenous modifications of the surface sialyl-residue pattern might be crucial to decide the final fate of the cells altered by positive͞negative selection interference or interaction with thymic lectins (3,35,36). The enzyme acts by mobilization of the sialyl residue, leading to either acquisition or loss of the residue by transferring it among glycoconjugates of the same cell, among different cells, or to the milieu.…”

Section: Discussionmentioning

confidence: 99%

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Thymocyte depletion in Trypanosoma cruzi infection is mediated by trans -sialidase-induced apoptosis on nurse cells complex

Mucci

Hidalgo

Mocetti

et al. 2002

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

101

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Trypanosoma cruzi, the causative agent of Chagas' disease, induces transient thymic aplasia early after infection-a phenomenon that stills lacks a molecular explanation. The parasite sheds an enzyme known as trans-sialidase (TS), which is able to direct transfer-sialyl residues among macromolecules. Because cell-surface sialylation is known to play a central role in the immune system, we tested whether the bloodstream-borne TS is responsible for the thymic alterations recorded during infection. We found that recombinant TS administered to naive mice was able to induce cell-count reduction mediated by apoptosis, mimicking cell subsets distribution and histologic findings observed during the acute phase of the infection. Thymocytes taken after TS treatment showed low response to Con A, although full ability to respond to IL-2 or IL-2 plus Con A was conserved, which resembles findings from infected animals. Alterations were found to revert several days after TS treatment. The administration of TS-neutralizing Abs to T. cruziinfected mice prevented thymus alterations. Results indicate that the primary target for the TS-induced apoptosis is the so-called ''nurse cell complex''. Therefore, we report here supporting evidence that TS is the virulence factor from T. cruzi responsible for the thymic alterations via apoptosis induction on the nurse cell complex, and that TS-neutralizing Abs elicitation during infection is associated with the reversion to thymic normal parameters.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Thymocyte depletion in Trypanosoma cruzi infection is mediated by trans -sialidase-induced apoptosis on nurse cells complex

Mucci

Hidalgo

Mocetti

et al. 2002

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

101

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“…In addition, the individual TCR⅐CD3 subunits could possess slightly distinct structures. These differences could be caused by developmentally acquired fundamental changes that distinguish the two cell types, including the glycosylation machinery (30,31) or chaperones. For instance, the inactivation of a sialyltransferase (ST3Gal-I) strongly reduced peripheral CD8 ϩ but not CD4 ϩ cell numbers (32).…”

Section: Fig 6 Characterization Of the Rw2-8c8 Antibody A Purifiedmentioning

confidence: 99%

Biochemical Differences in the αβ T Cell Receptor·CD3 Surface Complex between CD8+ and CD4+ Human Mature T Lymphocytes

Zapata

Schamel

Torres

et al. 2004

Journal of Biological Chemistry

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We have reported the existence of biochemical and conformational differences in the ␣␤ T cell receptor (TCR) complex between CD4 ؉ and CD8 ؉ CD3␥-deficient (␥ ؊ ) mature T cells. In the present study, we have furthered our understanding and extended the observations to primary T lymphocytes from normal (␥ ؉ ) individuals. Surface TCR⅐CD3 components from CD4 ؉ ␥ ؊ T cells, other than CD3␥, were detectable and similar in size to CD4 ؉ ␥ ؉ controls. Their native TCR⅐CD3 complex was also similar to CD4 ؉ ␥ ؉ controls, except for an ␣␤(␦⑀) 2 2 instead of an ␣␤␥⑀␦⑀ 2 stoichiometry. In contrast, the surface TCR␣, TCR␤, and CD3␦ chains of CD8 ؉ ␥ ؊ T cells did not possess their usual sizes. Using confocal immunofluorescence, TCR␣ was hardly detectable in CD8 ؉ ␥ ؊ T cells. Blue native gels (BN-PAGE) demonstrated the existence of a heterogeneous population of TCR⅐CD3 in these cells. Using primary peripheral blood T lymphocytes from normal (␥ ؉ ) donors, we performed a broad epitopic scan. In contrast to all other TCR⅐CD3-specific monoclonal antibodies, RW2-8C8 stained CD8 ؉ better than it did CD4 ؉ T cells, and the difference was dependent on glycosylation of the TCR⅐CD3 complex but independent of T cell activation or differentiation. RW2-8C8 staining of CD8 ؉ T cells was shown to be more dependent on lipid raft integrity than that of CD4 ؉ T cells. Finally, immunoprecipitation studies on purified primary CD4 ؉ and CD8 ؉ T cells revealed the existence of TCR glycosylation differences between the two. Collectively, these results are consistent with the existence of conformational or topological lineage-specific differences in the TCR⅐CD3 from CD4 ؉ and CD8 ؉ wild type T cells. The differences may be relevant for cis interactions during antigen recognition and signal transduction.␣␤ T lymphocytes recognize peptide-major histocompatibility complex ligands by means of a multimeric protein complex termed the ␣␤ T cell receptor (TCR) 1 CD3 complex (TCR⅐CD3). This structure is composed of a variable ␣␤ TCR dimer that binds antigens and three invariant dimers (CD3␥⑀, ␦⑀, and ) that are in charge of TCR⅐CD3 complex transport, stabilization, and signal transduction (1). The minimum stoichiometry, therefore, is believed to be ␣␤␥⑀␦⑀ 2 .Mature CD4 ϩ and CD8 ϩ ␣␤ T cells differ sharply in their major histocompatibility complex ligands, but their TCR⅐CD3 complex is believed to be qualitatively identical. The reduced ␣␤ TCR⅐CD3 staining levels observed in CD8 ϩ T cells, relative to CD4 ϩ T cells, were therefore reported as quantitative under this assumption (2). Unexpectedly, peripheral blood ␣␤ TCR⅐CD3 expression was shown to be more impaired in CD8 ϩ than in CD4 ϩ cells when CD3␥ (3, 4) or CD3␦ (5) was absent. These observations were followed by the description of conformational and biochemical differences in the TCR⅐CD3 complex between CD8 ϩ and CD4 ϩ CD3␥ deficient (␥ Ϫ ) T lymphocytes (6). Biosynthetic studies showed that CD8 ϩ but not CD4 ϩ ␥ Ϫ T cells lacked normal TCR␣. Instead, the CD4 ϩ ␥ Ϫ T cells contained a small ␣␤ hetero...

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“…It is also possible that one specific binding mode might be better accommodated because of the particular position at which a specific TCR docks with pMHCI (29 -31). Furthermore, the differentiation stage-related sialylation of the O-glycans associated with the stalk regions of CD8 proteins (18,19) may be compatible with one, but not another, binding orientation. Therefore, a given TCR⅐pMHCI complex may preferentially or exclusively interact with CD8␣␤ in one binding mode but not the other.…”

Section: Discussionmentioning

confidence: 97%

“…We reported previously that the extracellular domain of the CD8␤ subunit is critical for this enhanced efficiency (14) and that introduction of the CD8␤ stalk region is sufficient to confer a CD8␣␤-like co-receptor efficiency to the CD8␣␣ homodimer (17). In addition, the sialylation of the O-linked glycans in the CD8␤ stalk region is differentiation stage-dependent and may modulate the intrinsic activity of CD8␣␤ during the transition from double-positive (CD4 ϩ CD8 ϩ ) to single-positive (CD8 ϩ ) T cells (18,19). It was also reported that palmitoylation of a membrane-proximal cysteine residue in the cytoplasmic tail of CD8␤ during T-cell activation facilitates partition of CD8␣␤ heterodimers into lipid rafts, where it associates with the CD3 component of TCR complexes (20).…”

mentioning

confidence: 99%

CD8αβ Has Two Distinct Binding Modes of Interaction with Peptide-Major Histocompatibility Complex Class I

Chang

Tan

Hsu

2006

Journal of Biological Chemistry

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Interaction of CD8 (CD8␣␣ or CD8␣␤) with the peptide-major histocompatibility complex (MHC) class I (pMHCI) is critical for the development and function of cytolytic T cells. Although the crystal structure of CD8␣␣⅐pMHCI complex revealed that two symmetric CD8␣ subunits interact with pMHCI asymmetrically, with one subunit engaged in more extensive interaction than the other, the details of the interaction between the CD8␣␤ heterodimer and pMHCI remained unknown. The Ig-like domains of mouse CD8␣␤ and CD8␣␣ are similar in the size, shape, and surface electrostatic potential of their pMHCI-binding regions, suggesting that their interactions with pMHCI could be very similar. Indeed, we found that the CD8␣ variants CD8␣ R8A and CD8␣ E27A, which were functionally inactive as homodimers, could form an active co-receptor with wildtype (WT) CD8␤ as a CD8␣ R8A ␤ or CD8␣ E27A ␤ heterodimer. We also identified CD8␤ variants that could form active receptors with WT CD8␣ but not with CD8␣R8A . This observation is consistent with the notion that the CD8␤ subunit may replace either CD8␣ subunit in CD8␣␣⅐pMHCI complex. In addition, we showed that both anti-CD8␣ and anti-CD8␤ antibodies were unable to completely block the co-receptor activity of WT CD8␣␤. We propose that CD8␣␤ binds to pMHCI in at least two distinguishable orientations.CD8 is a co-receptor that enhances the presentation of peptide antigen complexed with MHC 2 class I molecule (pMHCI) to the T-cell receptor (1-3). Cell-surface CD8 is assembled as either CD8␣␣ homodimers or CD8␣␤ heterodimers (4 -6). Although CD8␣␣ and CD8␣␤ are structurally similar (7), they differ in tissue distribution, ligand specificity, and efficiency of antigen presentation (8, 9). Although CD8␣␤ is expressed primarily on the surface of ␣␤TCR ϩ thymocytes and peripheral T cells, CD8␣␣ has a much broader expression pattern, including the ␣␤TCR ϩ and ␥␦TCR ϩ intestinal intraepithelial lymphocytes, natural killer cells, and dendritic cells (9 -11). CD8␣␤ has been shown to be a more efficient co-receptor than CD8␣␣ for presentation of a given antigen (12-14). However, the underlying mechanism for the enhanced efficiency is not well understood. Both the extracellular domain and the cytoplasmic tail of the CD8␤ subunit have been implicated in providing increased efficiency of CD8␣␤ (12-16). We reported previously that the extracellular domain of the CD8␤ subunit is critical for this enhanced efficiency (14) and that introduction of the CD8␤ stalk region is sufficient to confer a CD8␣␤-like co-receptor efficiency to the CD8␣␣ homodimer (17). In addition, the sialylation of the O-linked glycans in the CD8␤ stalk region is differentiation stage-dependent and may modulate the intrinsic activity of CD8␣␤ during the transition from double-positive (CD4 ϩ CD8 ϩ ) to single-positive (CD8 ϩ ) T cells (18,19). It was also reported that palmitoylation of a membrane-proximal cysteine residue in the cytoplasmic tail of CD8␤ during T-cell activation facilitates partition of CD8␣␤ heterodimers into lipid rafts,...

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Developmentally Regulated Glycosylation of the CD8αβ Coreceptor Stalk Modulates Ligand Binding

Cited by 192 publications

References 54 publications

Thymocyte depletion in Trypanosoma cruzi infection is mediated by trans -sialidase-induced apoptosis on nurse cells complex

Thymocyte depletion in Trypanosoma cruzi infection is mediated by trans -sialidase-induced apoptosis on nurse cells complex

Biochemical Differences in the αβ T Cell Receptor·CD3 Surface Complex between CD8+ and CD4+ Human Mature T Lymphocytes

CD8αβ Has Two Distinct Binding Modes of Interaction with Peptide-Major Histocompatibility Complex Class I

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