HLA class I–associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children

Porritt, Rebecca A.; Paschold, Lisa; Rivas, Magali Noval; Cheng, Mary Hongying; Yonker, Lael M.; Chandnani, Harsha; Lopez, Merrick; Simnica, Donjetë; Schultheiß, Christoph; Santiskulvong, Chintda; Eyk, Jennifer E. Van; McCormick, John K.; Fasano, Alessio; Bahar, İvet; Binder, Mascha; Arditi, Moshe

doi:10.1172/jci146614

Cited by 157 publications

(199 citation statements)

References 74 publications

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“…Here, we reported the expansion of a TCR Vβ21.3+ T cell subset with an activated phenotype in as many as 75% of MIS-C patients. Vβ21.3+ T cell expansions were also reported in smaller numbers of MIS-C patients in two recent studies (13,37). In both Porritt et al and our study Vβ21.3+ T cell expansions appeared polyclonal as judged by the large number of TRBJ gene segments associated with TRBV11.2 and by the even distribution of the CDR3 domain.…”

Section: Discussionsupporting

confidence: 82%

“…Finally, given the rarity of MIS-C, there could be a genetic susceptibility to this post-infectious disease promoting hyperinflammatory reaction of adaptive immunity in response to SARS-CoV2 (16). We limited our analysis to classical HLA alleles, but did not find any significant association, even though a previous study reported an HLA-I bias in a smallest group of MIS-C patients (37). Of note our MIS-C samples were obtained in most of cases after anti-inflammatory treatments (see supplementary Table 1), and it is likely that those treatments affect the level of serum cytokines, which could have impacted the comparisons we made between clinical conditions, and the associations between cytokines and T cell expansions.…”

Section: Discussionmentioning

confidence: 87%

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Polyclonal expansion of TCR Vβ 21.3⁺CD4⁺and CD8⁺T cells is a hallmark of multisystem inflammatory syndrome in children

et al. 2021

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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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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 87%

Polyclonal expansion of TCR Vβ 21.3⁺CD4⁺and CD8⁺T cells is a hallmark of multisystem inflammatory syndrome in children

et al. 2021

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“…In contrast to febrile control patients without MIS-C and patients with mild MIS-C, TCR-sequencing analysis revealed enrichment of TRBV11-2, TRBV24-1, and TRBV11-3 gene segments in patients with severe MIS-C, and that TRBV11-2 enrichment, in particular, was associated with the development of a "cytokine storm" characterized by elevated levels of TNF-α, IFN-γ, IL-6, and IL-10 (9). Importantly, the authors went on to demonstrate that diversity in CDR3 and J gene usage was maintained and did not differ substantially amongst the patient groups (9). Because the CDR3 loop is the major determinant of antigen specificity for conventional peptide/MHC interactions, the observation that CDR3 diversity is maintained supports the authors' hypothesis that T cell expansion is being driven by a superantigen rather than a specific TCR/peptide/MHC interaction.…”

Section: Identification Of Vβ Restriction In Children With Mis-cmentioning

confidence: 88%

“…Although the authors do propose an in silico model for how SARS-CoV-2 may interact with the TCR and MHC molecule in a SAg fashion, in vitro and in vivo studies demonstrating a direct causal relationship still need to be performed (9).…”

Section: Identification Of Vβ Restriction In Children With Mis-cmentioning

confidence: 99%

“…The delayed response would indicate a mechanism that is separate from large scale T cell activation and the associated cytokine release that is classically seen in TSS. The authors hypothesize that this trigger may be a second exposure to SARS-CoV-2 in the absence of neutralizing antibody titers or residual viral particles in the intestinal tract (9). Another possibility follows a two-hit model whereby SARS-CoV-2 infection is the first-hit that non-specifically expands a polyclonal population of T cells.…”

Section: Concluding Thoughtsmentioning

confidence: 99%

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SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children

Kouo¹,

Chaisawangwong

2021

Journal of Clinical Investigation

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Multisystem Inflammatory Syndrome in Children (MIS-C) is a rare but deadly new disease in children that rapidly progresses to hyperinflammation, shock, and can lead to multiple organ failure if unrecognized. It has been found to be temporally associated with the COVID-19 pandemic and is often associated with SARS-CoV-2 exposure in children. In this issue of the JCI, Porritt and Paschold et al. identify restricted T cell receptor (TCR) β-chain variable domain (Vβ) usage in patients with severe MIS-C indicating a potential role for SARS-CoV-2 as a superantigen. These findings suggest that a blood test that determines the presence of specific TCR beta variable gene segments (TRBV) may identify patients at risk for severe MIS-C. Evolution of MIS-C as a new pediatric diseaseOver the past year, SARS-CoV-2 has been implicated in a variety of different disease processes. In addition to the respiratory syndrome now known as COVID-19, SARS-CoV-2 has also been implicated in formation of blood clots, rashes, neurological symptoms, and a post-infectious syndrome termed "long COVID." In sharp contrast to other respiratory viruses such as RSV and influenza, which cause a substantial disease burden in the pediatric population every year during the fall and winter months, the burden of disease for COVID-19 has fallen predominantly on adults.

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SARS‐CoV‐2‐related Multisystem Inflammatory Syndrome in Adult complicated by myocarditis and cardiogenic shock

et al. 2022

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Multisystem Inflammatory Syndrome in Adult (MIS-A) is a rare COVID-19 complication, presenting as fever with laboratory evidence of inflammation, severe illness requiring hospitalization and multisystem organ involvement. We report on a 25-year-old man presenting with fever, rash, abdominal pain, diarrhoea and vomiting following prior asymptomatic COVID-19 infection. He developed refractory shock and type 1 respiratory insufficiency requiring mechanical ventilation. Diagnostic testing revealed significant inflammation, anemia, thrombocytopenia, acute kidney injury, hepatosplenomegaly, colitis, lymphadenopathy and myocarditis necessitating inotropy. Ventilatory, vasopressor and inotropic support was weaned following pulse corticosteroids and intravenous immunoglobulins. Heart failure therapy was started. Short-term follow-up shows resolution of inflammation and cardiac dysfunction.

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HLA class I–associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children

Cited by 157 publications

References 74 publications

Polyclonal expansion of TCR Vβ 21.3⁺CD4⁺and CD8⁺T cells is a hallmark of multisystem inflammatory syndrome in children

Polyclonal expansion of TCR Vβ 21.3⁺CD4⁺and CD8⁺T cells is a hallmark of multisystem inflammatory syndrome in children

SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children

SARS‐CoV‐2‐related Multisystem Inflammatory Syndrome in Adult complicated by myocarditis and cardiogenic shock

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HLA class I–associated expansion of TRBV11-2 T cells in multisystem inflammatory syndrome in children

Cited by 157 publications

References 74 publications

Polyclonal expansion of TCR Vβ 21.3+CD4+and CD8+T cells is a hallmark of multisystem inflammatory syndrome in children

Polyclonal expansion of TCR Vβ 21.3+CD4+and CD8+T cells is a hallmark of multisystem inflammatory syndrome in children

SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children

SARS‐CoV‐2‐related Multisystem Inflammatory Syndrome in Adult complicated by myocarditis and cardiogenic shock

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Polyclonal expansion of TCR Vβ 21.3⁺CD4⁺and CD8⁺T cells is a hallmark of multisystem inflammatory syndrome in children

Polyclonal expansion of TCR Vβ 21.3⁺CD4⁺and CD8⁺T cells is a hallmark of multisystem inflammatory syndrome in children