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

Abstract

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.

TIM3+ TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C

“…When analyzing the dataset in individual patient samples, we found that approximately half of the MIS-C patients contributed to most TRBV11-2 + cells (Fig. 6 F), reminiscent of proportions described in previous studies (Moreews et al, 2021;Porritt et al, 2021;Ramaswamy et al, 2021). Nonetheless, in all MIS-C samples, significantly high proportions of the activated or proliferative cells (clusters 14 and 15) consisted of TRBV11-2expressing cells, supporting a similar disease course in all patients (Fig.…”

Characterization of SARS‐CoV‐2 and common cold coronavirus‐specific T‐cell responses in MIS‐C and Kawasaki disease children

“…It has been suggested that in MIS‐C patients, the T‐cell response is compromised and that a specific oligoclonal expansion of V beta 21.3 T cells defines the T‐cell repertoire [ 17 ]. Our data on the SARS‐CoV‐2‐specific T‐cell response neither suggest a defect in antiviral‐specific T cells nor were there differences in the virus‐specific T‐cell responses in the children with MIS‐C compared to convalescent controls following SARS‐CoV‐2 infection.…”

Multisystem Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Role of Oxidative Stress

“…Second, previous studies have shown that OS is involved in the acute stage of KD, caused by an overproduction of ROS for activated inflammatory cells ( 60 ). Although MIS-C has clinical similarities and cytokine profiles comparable to KD and TSS, recent studies suggest that there are differences in the type of activated cells during the immune response, observing a specific expansion of activated T lymphocytes that express the Vβ21.3 T cell receptor β chain variable region in CD4 and CD8 cells, something that differs in KD, TSS patients or SARS-COV-2 ( 61 ). In addition, the antibody response in MIS-C compared to adults with severe COVID-19 presents important differences, for example, a study showed that patients with MIS-C produced predominantly specific IgG antibodies (Abs) for the S protein but not for the N protein and in addition to a reduced neutralizing activity, while adult patients with COVID-19 presented Abs anti-S IgG, IgM and IgA, as well as Abs anti-N IgG, these results suggested that the immunological profile in MIS-C presents certain differential characteristics of COVID-19 in adults ( 62 ).…”