Unraveling a Hotspot for TCR Recognition on HLA-A2: Evidence Against the Existence of Peptide-independent TCR Binding Determinants

Gagnon, Susan J.; Borbulevych, O.Y.; Davis-Harrison, Rebecca L.; Baxter, Tiffany K.; Clemens, John R.; Armstrong, Kathryn M.; Turner, Richard V.; Damirjian, Marale; Biddison, William E.; Baker, Brian M.

doi:10.1016/j.jmb.2005.08.024

Cited by 36 publications

(47 citation statements)

References 55 publications

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“…The role of the TCR in this killing was more definitively addressed by using mutated B cell lymphoblastoid target cells previously shown to express an MHC-I mutant not recognizable by the TCR. In this experiment, we made use of the previous finding that the K66A mutation in the a1 helix of the HLA-A2 allele, in which the lysine residue is replaced by alanine, disrupts recognition by the TCR (24). These findings were consistent with an earlier study showing that this mutation disrupts recognition of HLA-A2 by a series of alloreactive CTLs (25).…”

Section: The Killing Of Lymphoma Cells By Anti-third-party Ctls Is Tcsupporting

confidence: 83%

“…First, the lymphoma cells are killed efficiently both by allogeneic and autologous anti-third-party CTLs. Second, TCR-independent killing is directly demonstrated by using malignant cells (H.My C1R) expressing mutated HLA-A2 at a position critical for TCR recognition (position K66) (24). Although this mutation disrupts recognition of peptide-MHC-I complexes by the TCR, these HLA-A2-mutated cells were depleted at a similar rate to that of H.My C1R cells expressing wt HLA-A2, when cocultured with anti-third-party CTLs.…”

Section: Discussionmentioning

confidence: 99%

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TCR-Independent Killing of B Cell Malignancies by Anti–Third-Party CTLs: The Critical Role of MHC–CD8 Engagement

Lask

Goichberg

Cohen

et al. 2011

The Journal of Immunology

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We previously demonstrated that anti–third-party CTLs (stimulated under IL-2 deprivation against cells with an MHC class I [MHC-I] background different from that of the host and the donor) are depleted of graft-versus-host reactivity and can eradicate B cell chronic lymphocytic leukemia cells in vitro or in an HU/SCID mouse model. We demonstrated in the current study that human allogeneic or autologous anti–third-party CTLs can also efficiently eradicate primary non-Hodgkin B cell lymphoma by inducing slow apoptosis of the pathological cells. Using MHC-I mutant cell line as target cells, which are unrecognizable by the CTL TCR, we demonstrated directly that this killing is TCR independent. Strikingly, this unique TCR-independent killing is induced through lymphoma MHC-I engagement. We further showed that this killing mechanism begins with durable conjugate formation between the CTLs and the tumor cells, through rapid binding of tumor ICAM-1 to the CTL LFA-1 molecule. This conjugation is followed by a slower second step of MHC-I–dependent apoptosis, requiring the binding of the MHC-I α2/3 C region on tumor cells to the CTL CD8 molecule for killing to ensue. By comparing CTL-mediated killing of Daudi lymphoma cells (lacking surface MHC-I expression) to Daudi cells with reconstituted surface MHC-I, we demonstrated directly for the first time to our knowledge, in vitro and in vivo, a novel role for MHC-I in the induction of lymphoma cell apoptosis by CTLs. Additionally, by using different knockout and transgenic strains, we further showed that mouse anti–third-party CTLs also kill lymphoma cells using similar unique TCR-independence mechanism as human CTLs, while sparing normal naive B cells.

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Section: The Killing Of Lymphoma Cells By Anti-third-party Ctls Is Tcsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

TCR-Independent Killing of B Cell Malignancies by Anti–Third-Party CTLs: The Critical Role of MHC–CD8 Engagement

Lask

Goichberg

Cohen

et al. 2011

The Journal of Immunology

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“…Solvent dielectric was set to 80 and the interior dielectric set to 10. The value of 10 for an interior dielectric was chosen based on our previous work (32) and is consistent with values used to reproduce experimental observations in other systems (60). We note, however, that although absolute values will change, our overall conclusions will be unaffected by the use of other interior dielectrics (see ref.…”

Section: Methodsmentioning

confidence: 89%

“…We computed this desolvation penalty for Arg65 and Lys66 in each TCR interface with A2, using a continuum electrostatics approach that yields the desolvation and coulombic energies associated with charge burial (27,43). We used this approach previously in studying TCR recognition of pMHC, validating it with mutational and binding studies (32). Across the 13 TCR-A2 interfaces, the average desolvation penalty for Arg65 was an unfavorable +2.0 kcal/mol, ranging from +0.5 to +3.8 kcal/mol (Fig.…”

mentioning

confidence: 99%

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

Blevins

Pierce

Singh

et al. 2016

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

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How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.T-cell receptor | peptide/MHC | structure | binding | MHC bias

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“…This CTL clone was tested in duplicate in the standard 5-h chromium-release assay for cytotoxicity against 51 Cr-labeled target cells that had been treated for 1 h with 0.1 mM peptide. The target cells were HLA-B8 + PHA-stimulated blasts that were raised by stimulating PBMCs with PHA, followed by propagation in IL-2-containing medium for up to 8 wk.…”

Section: Cytotoxicity Assaymentioning

confidence: 99%

A Structural Basis for Varied αβ TCR Usage against an Immunodominant EBV Antigen Restricted to a HLA-B8 Molecule

Gras

Wilmann

Chen

et al. 2012

The Journal of Immunology

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EBV is a ubiquitous and persistent human pathogen, kept in check by the cytotoxic T cell response. In this study, we investigated how three TCRs, which differ in their T cell immunodominance hierarchies and gene usage, interact with the same EBV determinant (FLRGRAYGL), bound to the same Ag-presenting molecule, HLA-B8. We found that the three TCRs exhibit differing fine specificities for the viral Ag. Further, via structural and biophysical approaches, we demonstrated that the viral Ag provides the greatest energetic contribution to the TCR–peptide-HLA interaction, while focusing on a few adjacent HLA-based interactions to further tune fine-specificity requirements. Thus, the TCR engages the peptide-HLA with the viral Ag as the main glue, such that neighboring TCR–MHC interactions are recruited as a supportive adhesive. Collectively, we provide a portrait of how the host’s adaptive immune response differentially engages a common viral Ag.

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Unraveling a Hotspot for TCR Recognition on HLA-A2: Evidence Against the Existence of Peptide-independent TCR Binding Determinants

Cited by 36 publications

References 55 publications

TCR-Independent Killing of B Cell Malignancies by Anti–Third-Party CTLs: The Critical Role of MHC–CD8 Engagement

TCR-Independent Killing of B Cell Malignancies by Anti–Third-Party CTLs: The Critical Role of MHC–CD8 Engagement

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

A Structural Basis for Varied αβ TCR Usage against an Immunodominant EBV Antigen Restricted to a HLA-B8 Molecule

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