Peptide-Independent Folding and CD8αα Binding by the Nonclassical Class I Molecule, Thymic Leukemia Antigen

Weber, Dominique A.; Attinger, Antoine; Kemball, Christopher C.; Wigal, Jerrod L.; Pohl, Jan; Xiong, Yongqiang; Reinherz, Ellis L.; Cheroutre, Hilde; Kronenberg, Mitchell; Jensen, Peter E.

doi:10.4049/jimmunol.169.10.5708

Cited by 28 publications

(29 citation statements)

References 47 publications

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“…The crystal structure of TL revealed that its putative ligand-binding groove is too narrow to accommodate peptides or other ligands (4). This corroborates with the stable folding of TL in the absence of added ligands (5)(6)(7)(8). TL binds to CD8␣␣ homodimers with unusually high affinity relative to the interaction of CD8␣␣ or CD8␣␤ molecules with classical MHC class I molecules (5,6).…”

Section: Cd8␣␣-mediated Intraepithelial Lymphocyte Snatching Of Thymisupporting

confidence: 56%

CD8αα-Mediated Intraepithelial Lymphocyte Snatching of Thymic Leukemia MHC Class Ib Molecules In Vitro and In Vivo

Pardigon

Takeda

Saunier

et al. 2006

The Journal of Immunology

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Thymic leukemia (TL) is a MHC class Ib molecule that interacts with CD8αα homodimers. CD8αα is abundantly expressed by intraepithelial T lymphocytes (IELs) located in close proximity to TL-expressing intestinal epithelial cells. In this study, we show that CD8αα+ IELs “snatch” TL from the plasma membrane of TL-expressing cells and express TL in its proper orientation on their own cell surface. TL snatching is enhanced by cross-linking of IEL TCRs in a phosphatidylinositol kinase-dependent manner, and results in overall alterations to the IEL cell surface detected by enhanced binding of peanut agglutinin lectin. Induction of bowel inflammation results in the presence of TL on IELs, probably via in vivo snatching, providing the initial evidence for the interaction of CD8αα IELs with intestinal cells.

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Section: Cd8␣␣-mediated Intraepithelial Lymphocyte Snatching Of Thymisupporting

confidence: 56%

CD8αα-Mediated Intraepithelial Lymphocyte Snatching of Thymic Leukemia MHC Class Ib Molecules In Vitro and In Vivo

Pardigon

Takeda

Saunier

et al. 2006

The Journal of Immunology

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“…To assess directly the importance of the T18 d ␣ 3 domain in the interaction with CD8␣␣, we generated T18 d , K b , and HLA-A2 chimeric recombinant proteins from bacterial inclusion bodies (10) by swapping their constituent ␣ 3 domains to form T18…”

Section: Resultsmentioning

confidence: 99%

“…A construct encoding the T18 d cDNA in the pET23a vector has been described elsewhere (10). A K b cDNA in the pET23a vector, an HLA-A2*0201 cDNA in the pHN1 vector, and a construct containing a human ␤ 2 m cDNA were a gift from Dr. J. Altman (Emory University, Atlanta, GA) (19).…”

Section: Dna Constructionsmentioning

confidence: 99%

“…The final PCR product was cloned into a TOPO-TA cloning kit (Invitrogen Life Technologies) and positive clones were sequenced. Finally, the T18 d ␣ 1 ␣ 2 /K b ␣ 3 DNA was NdeI-BamHI digested from the TOPO-TA vector and cloned in frame with a biotin-binding cassette (BSP) at the 3Ј end terminus into the pET23a vector as previously described (10) d cDNA in the pET23a vector was subjected to site directed mutagensis using the GeneEditor kit (Promega) with the mutagenic primers depicted in Table I. Finally, for the generation of K b recombinant proteins bearing mutations, site directed mutagenesis was performed using the Quick Change mutagenesis kit (Stratagene) with the mutagenic primers depicted in Table I.…”

Section: Dna Constructionsmentioning

confidence: 99%

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Molecular Basis for the High Affinity Interaction between the Thymic Leukemia Antigen and the CD8αα Molecule

Attinger

Devine

Wang-Zhu

et al. 2005

The Journal of Immunology

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The mouse thymic leukemia (TL) Ag is a nonclassical MHC class I molecule that binds with higher affinity to CD8αα than CD8αβ. The interaction of CD8αα with TL is important for lymphocyte regulation in the intestine. Therefore, we studied the molecular basis for TL Ag binding to CD8αα. The stronger affinity of the TL Ag for CD8αα is largely mediated by three amino acids on exposed loops of the conserved α3 domain. Mutant classical class I molecules substituted with TL Ag amino acids at these positions mimic the ability to interact with CD8αα and modulate lymphocyte function. These data indicate that small changes in the α3 domain of class I molecules potentially can have profound physiologic consequences.

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“…2B, our recent studies have demonstrated that TL molecules are transported to and stably expressed on the surfaces of TAP-deficient cells, such as RMA-S, 4,[10][11][12] and that most TL-specific CTLs recognize TL expressed in a TAP-independent manner. 12) Very recently, we have prepared TL tetramers free of antigenic peptides by way of peptide-independent folding with recombinant proteins produced in an Escherichia coli expression system, based on the report by Weber et al, 24) and showed that they bind to TL-specific CTLs in a TCR/CD3-dependent manner (Fig. 3A).…”

Section: Epitopes Recognized By Tl-specific Ctlsmentioning

confidence: 99%

Thymus‐leukemia antigen (TL) as a major histocompatibility complex (MHC) class Ib molecule and tumor‐specific antigen

Tsujimura¹,

Obata

Takahashi

2004

Cancer Science

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Mouse thymus-leukemia antigens (TL) belong to the family of major histocompatibility complex (MHC) class Ib antigens and have a unique mode of expression, i.e., in contrast to other MHC class Ib or Ia antigens, they are found restricted to the intestines in all mouse strains, but also in the thymus of certain strains (TL + strains). Nevertheless, a proportion of T lymphomas/leukemias in strains that do not express TL in the thymus (TL -strains) feature TL as a tumor antigen. TL was originally defined serologically, but subsequently we have succeeded in generating T cell receptor (TCR) α α α αβ β β β and γ γ γ γδ δ δ δ cytotoxic T lymphocytes (CTL) recognizing TL. By use of TL tetramers free from peptides and transfectants expressing various TL/H-2 chimeric molecules, we have been able to show that TL-specific CTL recognize the α α α α1/ α α α α2 domain of TL without any additional antigen molecules. We previously reported that one of TL's functions in the thymus is positive selection of TCRγ γ γ γδ δ δ δ CTL. Recent studies with TL tetramers revealed that they can bind to normal intestinal intraepithelial lymphocytes (iIEL) and thymocytes in a CD8-dependent, but TCR/CD3-independent manner, while their binding to TL-specific CTL is TCR/CD3-and CD8-dependent. The possible significance of these findings in relation to the roles of TL in the intestines is discussed. ouse thymus-leukemia antigens (TL) are major histocompatibility complex (MHC) class Ib (or nonclassical MHC class I) molecules encoded by closely related genes in the T region of mouse MHC. 1-5) TL genes have overall structures similar to MHC class Ia (classical MHC class I) genes, and show high homology among themselves, but they are only distantly related to other MHC class Ia and Ib genes, indicating the operation of natural selection to preserve the function of TL. 6)The products of TL genes are glycoproteins with molecular weights of approximately 45,000 daltons [7][8][9] and are expressed on the cell surface with β 2 -microglobulin (β 2 M), but they can be independently expressed transporters associated with antigen processing (TAP). 4,[10][11][12] A recent crystallographical analysis yielded the important finding that T18 d -TL has no antigen-binding groove wide enough to accommodate a peptide or lipid antigen, 13) in contrast to other MHC class Ia and Ib products. In normal mice, the expression of TL is restricted to the intestines in all mouse strains, but also the thymus of TL + strains (Fig. 1), 1,14,15) suggesting that TL plays a specialized role(s) in these organs, especially in the intestines. TL was originally described in 1963 as a serologically defined tumor-specific antigen, [16][17][18] since a proportion of T lymphomas/leukemias originating even from TL -strains (which do not express TL in the thymus) express TL (Fig. 1). We recently demonstrated that TL can also serve as a transplantation and tumor rejection antigen for T cells 19,20) and that both T cell receptor (TCR) αβ and γδ cytotoxic T lymphocytes (CTL) specific for TL can kill...

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Peptide-Independent Folding and CD8αα Binding by the Nonclassical Class I Molecule, Thymic Leukemia Antigen

Cited by 28 publications

References 47 publications

CD8αα-Mediated Intraepithelial Lymphocyte Snatching of Thymic Leukemia MHC Class Ib Molecules In Vitro and In Vivo

CD8αα-Mediated Intraepithelial Lymphocyte Snatching of Thymic Leukemia MHC Class Ib Molecules In Vitro and In Vivo

Molecular Basis for the High Affinity Interaction between the Thymic Leukemia Antigen and the CD8αα Molecule

Thymus‐leukemia antigen (TL) as a major histocompatibility complex (MHC) class Ib molecule and tumor‐specific antigen

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