The lew rat T cell response repertoire to an autoantigen and its regulation by anti-T cell receptor antibody

Antigen-specific CD8+ cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4+ T cells. CD4+ T cells predominantly have a helper immune role, but a cytotoxic CD4+ T-cell subset has been characterized, and we have studied the cytotoxic CD4+ T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4+ T-cell response that averages 3.6% of the total CD4+ T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4+ cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4+ T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4+ T cells thus parallels that of CD8+ subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7+ patients with CD4+ T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.

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Dominant Lesional T Cell Receptor Rearrangements Persist in Relapsing Psoriasis but are Absent from Nonlesional Skin: Evidence for a Stable Antigen-Specific Pathogenic T Cell Response in Psoriasis Vulgaris

Journal of Investigative Dermatology ◽

10.1046/j.0022-202x.2001.01494.x ◽

2001 ◽

Vol 117 (5) ◽

pp. 1296-1301 ◽

Cited By ~ 59

Author(s):

Sigrid Vollmer ◽

Antje Menssen ◽

Jörg C. Prinz

Keyword(s):

T Cell ◽

T Cell Receptor ◽

Cell Response ◽

Psoriasis Vulgaris ◽

Cell Receptor ◽

T Cell Response

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Class II major histocompatibility complex-peptide tetramer staining in relation to functional avidity and T cell receptor diversity in the mouse CD4+ T cell response to a rheumatoid arthritis-associated antigen

Arthritis & Rheumatism ◽

10.1002/art.21098 ◽

2005 ◽

Vol 52 (6) ◽

pp. 1885-1896 ◽

Cited By ~ 27

Author(s):

Michael T. Falta ◽

Andrew P. Fontenot ◽

Edward F. Rosloniec ◽

Frances Crawford ◽

Christina L. Roark ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Major Histocompatibility Complex ◽

T Cell ◽

T Cell Receptor ◽

Cell Response ◽

Cell Receptor ◽

T Cell Response ◽

Cd4 T Cell ◽

Tetramer Staining ◽

Histocompatibility Complex

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Selection of T cell receptor variable gene-encoded amino acids on the third binding site loop: a factor influencing variable chain selection in a T cell response

European Journal of Immunology ◽

10.1002/eji.1830250609 ◽

1995 ◽

Vol 25 (6) ◽

pp. 1529-1534 ◽

Cited By ~ 13

Author(s):

Margaret F. C. Callan ◽

Hugh T. Reyburn ◽

Paul Bowness ◽

Sarah Rowland-Jones ◽

John I. Bell ◽

...

Keyword(s):

Amino Acids ◽

T Cell ◽

Binding Site ◽

T Cell Receptor ◽

Cell Response ◽

Cell Receptor ◽

T Cell Response ◽

The Third ◽

Variable Gene ◽

Selection Of

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Tracking global changes induced in the CD4 T cell receptor repertoire by immunization with a complex antigen using short stretches of CDR3 protein sequence.

10.1101/001883 ◽

2014 ◽

Cited By ~ 3

Author(s):

Niclas Thomas ◽

Katharine Best ◽

Mattia Cinelli ◽

Shlomit Reich-Zeliger ◽

Hila Gal ◽

...

Keyword(s):

Amino Acids ◽

T Cell ◽

T Cell Receptor ◽

Cell Response ◽

Cell Receptor ◽

T Cell Response ◽

Cd4 T Cell ◽

Receptor Repertoire ◽

T Cell Receptor Repertoire ◽

Cell Receptor Repertoire

The clonal theory of adaptive immunity proposes that immunological responses are encoded by increases in the frequency of lymphocytes carrying antigen-specific receptors. In this study, we measure the frequency of different TcRs in CD4+ T cell populations of mice immunized with a complex antigen, killed Mycobacterium tuberculosis, using high throughput parallel sequencing of the TcR beta chain. In order to track the changes induced by immunization within this very heterogeneous repertoire, the sequence data were classified by counting the frequency of different clusters of short (3 or 4) continuous stretches of amino acids within the CDR3 repertoire of different mice. Both unsupervised (hierarchical clustering) and supervised (support vector machine) analysis of these different distributions of sequence clusters differentiated between immunised and unimmunised mice with 100\% efficiency. The CD4+ T cell receptor repertoires of mice 5 and 14 days post immunisation were clearly different from that of unimmunised mice, but were not distinguishable from each other. However, the repertoires of mice 60 days post immunisation were distinct both from naive mice, and the day 5/14 animals. Our results reinforce the remarkable diversity of the T cell receptor repertoire, resulting in many diverse private TcRs contributing to the T cell response even in genetically identical mice responding to the same antigen. Finally, specific motifs defined by short sequences of amino acids within the CDR3 region may have a major effect on TcR specificity. The results of this study provide new insights into the properties of the CD4+ adaptive T cell response.

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The T cell receptor repertoire reflects the dynamics of the immune response to vaccination

10.1101/2021.12.09.471735 ◽

2021 ◽

Author(s):

Kevin Mohammed ◽

Austin Meadows ◽

Sandra Hatem ◽

Viviana Simon ◽

Anitha D Jayaprakash ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Influenza Vaccine ◽

T Cell Receptor ◽

Cell Response ◽

Cell Receptor ◽

Physical Symptoms ◽

T Cell Response ◽

Tcr Repertoire

Early, high-resolution metrics are needed to ascertain the immune response to vaccinations. The T cell receptor (TCR), a heterodimer of one α and one β chain, is a promising target, with the complete TCR repertoire reflecting the T cells present in an individual. To this end, we developed Tseek, an unbiased and accurate method for profiling the TCR repertoire by sequencing the TCR α and β chains and developing a suite of tools for repertoire analysis. An added advantage is the ability to non-invasively analyze T cells in peripheral blood mononuclear cells (PBMCs). Tseek and the analytical suite were used to explore the T cell response to both the COVID-19 mRNA vaccine (n=9) and the seasonal inactivated Influenza vaccine (n=5) at several time points. Neutralizing antibody titers were also measured in the covid vaccine samples. The COVID-19 vaccine elicited a broad T cell response involving multiple expanded clones, whereas the Influenza vaccine elicited a narrower response involving fewer clones. Many distinct T cell clones responded at each time point, over a month, providing temporal details lacking in the antibody measurements, especially before the antibodies are detectable. In individuals recovered from a SARS-CoV-2 infection, the first vaccine dose elicited a robust T cell response, while the second dose elicited a comparatively weaker response, indicating a saturation of the response. The physical symptoms experienced by the recipients immediately following the vaccinations were not indicative of the TCR/antibody responses, while a weak TCR response seemed to presage a weak antibody response. We also found that the TCR repertoire acts as an individual fingerprint: donors of blood samples taken years apart could be identified solely based upon their TCR repertoire, hinting at other surprising uses the TCR repertoire may have. These results demonstrate the promise of TCR repertoire sequencing as an early and sensitive measure of the adaptive immune response to vaccination, which can help improve immunogen selection and optimize vaccine dosage and spacing between doses.

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