The Study of High-Affinity TCRs Reveals Duality in T Cell Recognition of Antigen: Specificity and Degeneracy

Donermeyer, David L.; Weber, K. Scott; Kranz, David M.; Allen, Paul M.

doi:10.4049/jimmunol.177.10.6911

Cited by 45 publications

(44 citation statements)

References 57 publications

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“…43,59 Moreover, cross-reactivity has been also observed for high-affinity TCRs and therefore might be a general property of T-cell recognition. [60][61][62] This is certainly an important issue for the development of immunotherapies using allorestricted peptide-specific T cells. Although FMNL1-PP2 peptide-specific T cells are highly specific and cross-reactivity has been observed only exceptionally, further investigations in vitro and in vivo are necessary to clarify if other peptides and MHC molecules might be recognized by FMNL1-PP2-specific T cells.…”

Section: Discussionmentioning

confidence: 99%

Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies

Schuster¹,

Busch²,

Eppinger³

et al. 2007

Blood

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Cell-based immunotherapy in settings of allogeneic stem cell transplantation or donor leukocyte infusion has curative potential, especially in hematologic malignancies. However, this approach is severely restricted due to graft-versus-host disease (GvHD). This limitation may be overcome if target antigens are molecularly defined and effector cells are specifically selected. We chose formin-related protein in leukocytes 1 (FMNL1) as a target antigen after intensive investigation of its expression profile at the mRNA and protein levels. Here, we confirm re- IntroductionAlthough it is controversially discussed whether adaptive immune responses in tumor-bearing hosts play a role in controlling growth and recurrence of human tumors, 1,2 T cells can be converted to highly efficient killers of tumors. Donor leukocyte infusions (DLIs) are responsible for a graft-versus-leukemia effect (GvL) after allogeneic stem-cell transplantation (SCT), representing a therapeutic option with curative potential in different diseases at advanced stages. 3 Although GvL responses have also been shown for low-grade lymphomas, improvement of long-term survival after allogeneic transplantation has not been demonstrated in these patients. [4][5][6][7][8] This can be attributed primarily to the high treatmentassociated mortality due to transfer of T cells recognizing allogeneic minor histocompatibility (MHC) antigens, thereby causing potentially life-threatening graft-versus-host disease (GvHD). For broader applicability of this therapeutic option, it is therefore essential to reduce the risk of detrimental GvHD.One approach to gain a tumor-specific effect while significantly reducing the risk of GvHD is to generate allorestricted T cells with specificity for epitopes derived from tumor-associated antigens (TAAs). 9 Such allorestricted peptide-specific T cells may display high avidity toward MHC-presented TAAs, because they have not been negatively selected in the thymus. Moreover, they can be isolated by tetramers and cloned by limiting dilution to identify the specific TCR responsible for tumor-selective killing. 10 The isolation of a TCR with defined specificity for TAAs facilitates genetic TCR transfer into T-cell lines, 11-14 allowing major expansion of tumor-specific T cells.The choice of an appropriate target antigen is of fundamental importance for the success of an antitumor immunotherapeutic approach. So far, there is no universal antigen that serves as a target antigen in a broad range of malignancies. Many tumor-specific antigens are derived from aberrant expression of cell type-specific proteins and are expressed only in a restricted number of tumor types, limiting the tumors that can be treated. However, even the presence of a suitable antigen does not guarantee effective antigen recognition, because tumor cells evade immune recognition by down-regulation of the specific target or by inhibition of MHC class I-restricted antigen presentation. Thus, the level of epitope presentation in the context of classical or nonclassical MHC...

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Section: Discussionmentioning

confidence: 99%

Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies

Schuster¹,

Busch²,

Eppinger³

et al. 2007

Blood

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“…An exception is an analogous study using a high affinity TCR against a class II ligand. Substitution of several Hb peptide residues involved in binding to I-E k resulted in reduced binding by the high affinity TCR (45).…”

Section: Discussionmentioning

confidence: 99%

Different Strategies Adopted by Kb and Ld to Generate T Cell Specificity Directed against Their Respective Bound Peptides

Bowerman

Colf

García

et al. 2009

Journal of Biological Chemistry

Self Cite

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Mouse T cell clone 2C recognizes two different major histocompatibility (MHC) ligands, the self MHC K b and the allogeneic MHC L d . Two distinct peptides, SIY (SIYRYYGL) and QL9 (QLSPFPFDL), act as strong and specific agonists when bound to K b and L d , respectively. To explore further the mechanisms involved in peptide potency and specificity, here we examined a collection of single amino acid peptide variants of SIY and QL9 for 1) T cell activity, 2) binding to their respective MHC, and 3) binding to the 2C T cell receptor (TCR) and high affinity TCR mutants. Characterization of SIY binding to MHC K b revealed significant effects of three SIY residues that were clearly embedded within the K b molecule. In contrast, QL9 binding to MHC L d was influenced by the majority of peptide side chains, distributed across the entire length of the peptide. Binding of the SIY-K b complex to the TCR involved three SIY residues that were pointed toward the TCR, whereas again the majority of QL9 residues influenced binding of TCRs, and thus the QL9 residues had impacts on both L d and TCR binding. In general, the magnitude of T cell activity mediated by a peptide variant was influenced more by peptide binding to MHC than by binding the TCR, especially for higher affinity TCRs. Findings with both systems, but QL9-L d in particular, suggest that many single-residue substitutions, introduced into peptides to improve their binding to MHC and thus their vaccine potential, could impair T cell reactivity due to their dual impact on TCR binding. Elimination of virus-infected cells or cancer cells by cytotoxic T lymphocytes is governed by interactions between an␣␤ heterodimeric T cell receptor (TCR) 2 and a short, processed, peptide that is bound to a product of the major histocompatibility complex (peptide-MHC) (1). It is well established that a single TCR is capable of recognizing multiple distinct peptide-MHC ligands while maintaining exquisite specificity for each (2, 3).Ultimately, both the specificity and potency of a peptide derives from its interactions with the MHC product and with the TCR. The importance of understanding the role of each peptide residue in eliciting T cell activity can be seen in the considerable effort toward the development of peptide vaccines for the treatment of infection diseases or cancer (4). These efforts have often attempted to enhance the activity of a peptide by generating peptide variants with improved binding for the MHC product (5-7). This approach is absolutely dependent on the ability of T cells to react well not only with the peptide variant but with the native peptide that is presented by infected cells or by the cancer cells. In this regard, it is important to understand whether changes to a peptide impact not only MHC product binding but also binding by the TCR.Multiple genes and extensive polymorphism in the MHC enable different MHC products to bind and present a distinct set of peptides (8). For example, the mouse MHC products K b and L d differ by 30 amino acid residues in the peptide...

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“…In a second study, T cells expressing an engineered highaffinity 3.L2 TCR (25 nM) remarkably had unchanged antigen sensitivity and retained antigen specificity [23]. Functional testing of a large set of single substituted TCR contact residue Hb peptides revealed a large increase in the number of stimulatory peptides.…”

Section: Influence Of a Subtle Change In The Mhc Binding Of A Ligand mentioning

confidence: 99%

Polyspecificity of T cell and B cell receptor recognition

Wucherpfennig

Allen

Celada

et al. 2007

Seminars in Immunology

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197

171

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A recent workshop discussed the recognition of multiple distinct ligands by individual T cell and B cell receptors and the implications of this discovery for lymphocyte biology. The workshop recommends general use of the term polyspecificity because it emphasizes two fundamental aspects, the inherent specificity of receptor recognition and the ability to recognize multiple ligands. Many different examples of polyspecificity and the structural mechanisms were discussed, and the group concluded that polyspecificity is a general, inherent feature of TCR and antibody recognition. This review summarizes the relevance of polyspecificity for lymphocyte development, activation and disease processes.

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The Study of High-Affinity TCRs Reveals Duality in T Cell Recognition of Antigen: Specificity and Degeneracy

Cited by 45 publications

References 57 publications

Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies

Allorestricted T cells with specificity for the FMNL1-derived peptide PP2 have potent antitumor activity against hematologic and other malignancies

Different Strategies Adopted by Kb and Ld to Generate T Cell Specificity Directed against Their Respective Bound Peptides

Polyspecificity of T cell and B cell receptor recognition

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