T cell repertoire to citrullinated self-peptides in healthy humans is not confined to the HLA-DR SE alleles; Targeting of citrullinated self-peptides presented by HLA-DP4 for tumour therapy

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

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Highly Restricted T Cell Repertoire Shaped by a Single Major Histocompatibility Complex–Peptide Ligand in the Presence of a Single Rearranged T Cell Receptor β Chain

Journal of Experimental Medicine ◽

10.1084/jem.188.5.897 ◽

1998 ◽

Vol 188 (5) ◽

pp. 897-907 ◽

Cited By ~ 23

Author(s):

Yoshinori Fukui ◽

Osamu Hashimoto ◽

Ayumi Inayoshi ◽

Takahiro Gyotoku ◽

Tetsuro Sano ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Positive Selection ◽

Peptide Ligand ◽

T Cell Repertoire ◽

Major Histocompatibility ◽

Cell Repertoire ◽

Histocompatibility Complex ◽

Self Peptides ◽

Selection Of

The T cell repertoire is shaped by positive and negative selection of thymocytes through the interaction of α/β-T cell receptors (TCR) with self-peptides bound to self-major histocompatibility complex (MHC) molecules. However, the involvement of specific TCR-peptide contacts in positive selection remains unclear. By fixing TCR-β chains with a single rearranged TCR-β irrelevant to the selecting ligand, we show here that T cells selected to mature on a single MHC–peptide complex express highly restricted TCR-α chains in terms of Vα usage and amino acid residue of their CDR3 loops, whereas such restriction was not observed with those selected by the same MHC with diverse sets of self-peptides including this peptide. Thus, we visualized the TCR structure required to survive positive selection directed by this single ligand. Our findings provide definitive evidence that specific recognition of self-peptides by TCR could be involved in positive selection of thymocytes.

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Collagen Specific T-Cell Repertoire and HLA-DR Alleles: Biomarkers of Active Refractory Rheumatoid Arthritis

EBioMedicine ◽

10.1016/j.ebiom.2015.11.019 ◽

2015 ◽

Vol 2 (12) ◽

pp. 2037-2045 ◽

Cited By ~ 17

Author(s):

Gabriele Di Sante ◽

Barbara Tolusso ◽

Anna Laura Fedele ◽

Elisa Gremese ◽

Stefano Alivernini ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cell ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Hla Dr ◽

Refractory Rheumatoid Arthritis

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Recognition Requirements for the Positive Selection of the T Cell Repertoire: A Role of Self-Peptides and Major Histocompatibility Complex Pockets

Molecular Mechanisms of Immunological Self-Recognition ◽

10.1016/b978-0-12-053750-1.50012-x ◽

1993 ◽

pp. 105-114

Author(s):

JANKO NIKOLIĆ-ŽUGIĆ ◽

MICHAEL J. BEVAN

Keyword(s):

Major Histocompatibility Complex ◽

T Cell ◽

Positive Selection ◽

T Cell Repertoire ◽

Major Histocompatibility ◽

Cell Repertoire ◽

Histocompatibility Complex ◽

Self Peptides ◽

Selection Of

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Presentation of a self-peptide for in vivo tolerance induction of CD4+ T cells is governed by a processing factor that maps to the class II region of the major histocompatibility complex locus.

Journal of Experimental Medicine ◽

10.1084/jem.182.5.1481 ◽

1995 ◽

Vol 182 (5) ◽

pp. 1481-1491 ◽

Cited By ~ 13

Author(s):

E V Fedoseyeva ◽

R C Tam ◽

P L Orr ◽

M R Garovoy ◽

G Benichou

Keyword(s):

T Cells ◽

T Cell ◽

Mhc Class Ii ◽

Tolerance Induction ◽

Class Ii ◽

The Self ◽

T Cell Repertoire ◽

Cell Repertoire ◽

Mhc Class Ii Molecules ◽

Self Peptides

Self-proteins are regularly processed for presentation to autoreactive T cells in association with both class I and class II major histocompatibility complex (MHC) molecules. The presentation of self-peptides plays a crucial role in the acquisition of T cell repertoire during thymic selection. We previously reported that the self-MHC class I peptide Ld 61-80 was immunogenic in syngeneic B10.A mice (H-2a). We showed that despite its high affinity for self-MHC class II molecules, Ld 61-80 peptide failed to induce elimination of autoreactive CD4+ T cells, presumably due to incomplete processing and presentation in the B10.A's developing thymus (cryptic-self peptide). In this report, we showed that the cryptic phenotype was not an intrinsic property of the self-peptide Ld 61-80 since it was found to be naturally presented and subsequently tolerogenic in BALB/c mice (H-2d) (dominant self-peptide). In addition, the self-peptide Ld 61-80 was found to be immunogenic in different H-2a mice while it was invariably tolerogenic in H-2d mice regardless of their background genes. We observed that Ld 61-80 bound equally well to H-2d and H-2k MHC class II molecules. Also, no correlation was found between the quantity of self-Ld protein and the tolerogenicity of Ld 61-80. Surprisingly, Ld 61-80 was not naturally presented in (H-2d x H-2a) F1 mice, indicating that the H-2a MHC locus contained a gene that impaired the presentation of the self-peptide. Analyses of T cell responses to the self-peptide in several H-2 recombinant mice revealed that the presentation of Ld 61-80 was controlled by genes that mapped to a 170-kb portion of the MHC class II region. This study shows that (a) endogenously processed self-peptides presented by MHC class II molecules are involved in shaping the CD4+ T cell repertoire in the thymus; (b) The selection of self-peptides for presentation by MHC class II molecules to nascent autoreactive T cells is influenced by nonstructural MHC genes that map to a 170-kb portion of the MHC class II region; and (c) the MHC locus of H-2a mice encodes factors that prevent or abrogate the presentation by MHC class II molecules of the self-peptide Ld 61-80. These findings may have important implications for understanding the molecular mechanisms involved in T cell repertoire acquisition and self-tolerance induction.

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