The discriminatory power of the T cell receptor

T cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self pMHC antigens. Although the discriminatory power of the TCR is widely believed to be near-perfect, technical difficulties have hampered efforts to precisely quantify it. Here, we describe a method for measuring very low TCR/pMHC affinities, and use it to measure the discriminatory power of the TCR, and the factors affecting it. We find that TCR discrimination, although enhanced compared with conventional cell-surface receptors, is imperfect: primary human T cells can respond to pMHC with affinities as low as KD ~1 mM. The kinetic proofreading mechanism fit our data, providing the first estimates of both the time delay (2.8 s) and number of biochemical steps (2.67) that are consistent with the extraordinary sensitivity of antigen recognition. Our findings explain why self pMHC frequently induce autoimmune diseases and anti-tumour responses, and suggest ways to modify TCR discrimination.

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T Cell Receptor Transfection Shows Non-HLA-Restricted Recognition of Nickel by CD8+ Human T Cells to be Mediated by αβ T Cell Receptors

Journal of Investigative Dermatology ◽

10.1046/j.1523-1747.2003.12405.x ◽

2003 ◽

Vol 121 (3) ◽

pp. 496-501 ◽

Cited By ~ 10

Author(s):

Corinne Moulon ◽

Yoanna Choleva ◽

Hermann-Josef Thierse ◽

Doris Wild ◽

Hans Ulrich Weltzien

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

T Cell Receptors ◽

Cell Receptor ◽

Cell Receptors ◽

Human T Cells

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The discriminatory power of the T cell receptor

10.1101/2020.11.16.384495 ◽

2020 ◽

Cited By ~ 1

Author(s):

Anna Huhn ◽

Daniel B. Wilson ◽

P. Anton van der Merwe ◽

Omer Dushek

Keyword(s):

T Cell ◽

T Cell Receptor ◽

T Cell Receptors ◽

Cell Receptor ◽

Discriminatory Power ◽

Published Data ◽

Discrimination Power ◽

Cell Responses ◽

Kinetic Proofreading ◽

Striking Contrast

AbstractT cells use their T-cell receptors (TCRs) to discriminate between lower-affinity self and higher-affinity non-self pMHC antigens. The strength of this discrimination and the mechanisms that produce it remain controversial. Although a large number of mouse and human TCRs have now been characterised, they have not been used to precisely quantitate discrimination. Here, we systematically quantify the discrimination of TCRs using a discrimination power (α). Early influential studies on three mouse TCRs suggested that discrimination was nearly perfect (α ~ 9.0). In striking contrast, our analysis of published data on other mouse and human TCRs, and more recent data on the original mouse TCRs, produced significantly lower discrimination (α = 2.0). Although not perfect, the discriminatory power of TCR was greater than that of conventional receptors such as cytokine receptors, GPCRs, RTKs, and CARs (α ≤ 1). The revised discriminatory power of the TCR is readily explained by a kinetic proofreading mechanisms, and accounts for the ability of low affinity self-antigens to stimulate autoimmune and anti-tumour T cell responses.

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Characterization of human T cells reactive with the Mycoplasma arthritidis-derived superantigen (MAM): generation of a monoclonal antibody against V beta 17, the T cell receptor gene product expressed by a large fraction of MAM-reactive human T cells.

Journal of Experimental Medicine ◽

10.1084/jem.174.4.891 ◽

1991 ◽

Vol 174 (4) ◽

pp. 891-900 ◽

Cited By ~ 44

Author(s):

S M Friedman ◽

M K Crow ◽

J R Tumang ◽

M Tumang ◽

Y Q Xu ◽

...

Keyword(s):

Monoclonal Antibody ◽

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cell Activity ◽

Cell Receptor ◽

Cytotoxic T Cell ◽

Mycoplasma Arthritidis ◽

Human T Cells

While all known microbial superantigens are mitogenic for human peripheral blood lymphocytes (PBL), the functional response induced by Mycoplasma arthritidis-derived superantigen (MAM) is unique in that MAM stimulation of PBL consistently results in T cell-dependent B cell activation characterized by polyclonal IgM and IgG production. These immunostimulatory effects of MAM on the humoral arm of the human immune system warranted a more precise characterization of MAM-reactive human T cells. Using an uncloned MAM reactive human T cell line as immunogen, we have generated a monoclonal antibody (mAb) (termed C1) specific for the T cell receptor V beta gene expressed by the major fraction of MAM-reactive human T cells, V beta 17. In addition, a V beta 17- MAM-reactive T cell population exists, assessed by MAM, induced T cell proliferation and cytotoxic T cell activity. mAb C1 will be useful in characterizing the functional properties of V beta 17+ T cells and their potential role in autoimmune disease.

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Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4-, CD8- T lymphocytes.

Journal of Experimental Medicine ◽

10.1084/jem.168.5.1899 ◽

1988 ◽

Vol 168 (5) ◽

pp. 1899-1916 ◽

Cited By ~ 147

Author(s):

J A Bluestone ◽

R Q Cron ◽

M Cotterman ◽

B A Houlden ◽

L A Matis

Keyword(s):

T Cells ◽

T Cell ◽

Cell Line ◽

Gene Segment ◽

Cell Receptor ◽

Gamma Delta ◽

Human T Cells ◽

T Cell Lines ◽

Gamma Delta T Cell ◽

Delta Cells

Analyses of TCR-bearing murine and human T cells have defined a unique subpopulation of T cells that express the TCR-gamma/delta proteins. The specificity of TCR-gamma/delta T cells and their role in the immune response have not yet been elucidated. Here we examine alloreactive TCR-gamma/delta T cell lines and clones that recognize MHC-encoded antigens. A BALB/c nu/nu (H-2d)-derived H-2k specific T cell line and derived clones were both cytolytic and released lymphokines after recognition of a non-classical H-2 antigen encoded in the TL region of the MHC. These cells expressed the V gamma 2/C gamma 1 protein in association with a TCR-delta gene product encoded by a Va gene segment rearranged to two D delta and one J delta variable elements. A second MHC-specific B10 nu/nu (H-2b) TCR-gamma/delta T cell line appeared to recognize a classical H-2D-encoded MHC molecule and expressed a distinct V gamma/C gamma 4-encoded protein. These data suggest that many TCR-gamma/delta-expressing T cells may recognize MHC-linked antigens encoded within distinct subregions of the MHC. The role of MHC-specific TCR-gamma/delta cells in immune responses and their immunological significance are discussed.

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