Frequent Contribution of T Cell Clonotypes with Public TCR Features to the Chronic Response Against a Dominant EBV-Derived Epitope: Application to Direct Detection of Their Molecular Imprint on the Human Peripheral T Cell Repertoire

Abstract

In an attempt to provide a global picture of the TCR repertoire diversity of a chronic T cell response against a common Ag, we performed an extensive TCR analysis of cells reactive against a dominant HLA-A2-restricted EBV epitope (hereafter referred to as GLC/A2), obtained after sorting PBL or synovial fluid lymphocytes from EBV-seropositive individuals using MHC/peptide multimers. Although TCR β-chain diversity of GLC/A2+ T cells was extensive and varied greatly from one donor to another, we identified in most cell lines several recurrent Vβ subsets (Vβ2, Vβ4, and Vβ16 positive) with highly conserved TCRβ complementarity-determining region 3 (CDR3) length and junctional motifs, which represented from 11 to 98% (mean, 50%) of GLC/A2-reactive cells. While TCR β-chains expressed by these subsets showed limited CDR1, CDR2, and CDR3 homology among themselves, their TCR α-chains comprised the same TCRAV region, thus suggesting hierarchical contribution of TCR α-chain vs TCR β-chain CDR to recognition of this particular MHC/peptide complex. The common occurrence of T cell clonotypes with public TCR features within GLC/A2-specific T cells allowed their direct detection within unsorted PBL using ad hoc clonotypic primers. These results, which suggest an unexpectedly high contribution of public clonotypes to the TCR repertoire against a dominant epitope, have several implications for the follow-up and modulation of T cell-mediated immunity.

A Large Number of T Lymphocytes Recognize Moloney-Murine Leukemia Virus-Induced Antigens, but a Few Mediate Long-Lasting Tumor Immunosurveillance

“…However, despite alternative V␤ T cell priming, the immune response to M-MuLV-induced Ags is dominated by the almost exclusive expansion of T cell clones sharing V␤5 gene segments (17). These findings confirm the observations that the massive CD8 ϩ T cell expansion during viral infection (1, 2) in many cases is accompanied by the selection of a V␤ restricted T cell repertoire (7)(8)(9)(10)(11).…”

“…Furthermore, T cell responses often appear limited to a single encoded immunodominant peptide which generally stimulates a large number of specific CTL, while subdominant epitopes elicit T cell response that do not offer a high protection level against pathogens (5,6). Clonotypic analysis of CD8 T cell response in many cases provides evidence that immunodominant determinants are recognized by a restricted T cell repertoire that uses a limited number of TCRV␤ and/or V␣ domains (7)(8)(9)(10)(11).…”

Distinct TCRAV and TCRBV repertoire and CDR3 sequence of T lymphocytes clonally expanded in blood and GVHD lesions after human allogeneic bone marrow transplantation

“…There is a report describing that chronic antigen stimulation causes limited TCRBV usage and highly conserved CDR3 sequences between distinct individuals, using an MHC/A2-restricted EBV-derived peptide tetramer technique. 34 It has been also demonstrated that CDR3 sequence homology only exists for T cells using the same TCRBV segment. 34 TCRBV segments used by T cell clones in GVHD skin lesions were different between patients UPN01 and UPN02.…”

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

“…The variable degree of diversity of the TCR repertoire observed during chronic virus infections might be related to the experimental strategies used in various studies. Many studies have analyzed the TCR repertoire in T cell lines and/or clones obtained in vitro from a limited number of subjects (21,22) and/or have been based on the use of an incomplete panel of anti-Vb mAbs (14,15,(21)(22)(23), raising the question of to what extent these data were representative of the in vivo situation. With regard to the direct sequencing of the TCR b-chain by anchored PCR in ex vivo Ag-specific sorted cells (19,20,24), it is possible that the TCR repertoire diversity might be underestimated, as the degree of diversity measured will be dependent upon the extent of sequencing with the potential for preferential detection of dominant CD8 T cell clonotypes.…”