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. 2023 Dec 5:11:1235342.
doi: 10.3389/fped.2023.1235342. eCollection 2023.

Multisystem inflammatory syndrome in children characterized by enhanced antigen-specific T-cell expression of cytokines and its reversal following recovery

Nathella Pavan Kumar #  1 , Kadar M Abbas #  2 , Rachel M Renji  2 , Aishwarya Venkataraman  3 , Arul Nancy  2 , Poovazhagi Varadarjan  4 , Elilarasi Selladurai  4 , Thankgavelu Sangaralingam  5 , Ramya Selvam  5 , Akshith Thimmaiah  5 , Suresh Natarajan  6 , Ganesh Ramasamy  6 , Syed Hissar  3 , Uma Devi Ranganathan  1 , Thomas B Nutman  7 , Subash Babu  2   7
Affiliations

Multisystem inflammatory syndrome in children characterized by enhanced antigen-specific T-cell expression of cytokines and its reversal following recovery

Nathella Pavan Kumar et al. Front Pediatr. .

Abstract

Background: Multisystem inflammatory syndrome (MIS) in children is considered to be a post-infectious complication of COVID-19. T-cell responses in children with this condition have not been well-studied.

Methods: We aimed to study the immune responses in children with MIS in comparison to children with acute COVID-19 and children with other infections. Whole blood was stimulated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific antigens and flow cytometry was performed to examine CD4+ and CD8+ T-cell responses.

Results: Children with MIS had higher frequencies of CD4+ and CD8+ T cells expressing cytokines at baseline and upon SARS-CoV-2 antigen-specific stimulation in comparison to children with COVID-19 and/or other infections. Children with COVID-19 also exhibited higher frequencies of CD4+ and CD8+ T cells expressing cytokines at baseline and upon SARS-CoV-2 antigen-specific stimulation in comparison to children with other infections. At 6-9 months following treatment and recovery, this enhanced response against SARS-CoV-2 antigens was down modulated in children with MIS.

Conclusion: Our study, therefore, provides evidence of enhanced activation of CD4+ and CD8+ T-cell responses in children with MIS and reversal following recovery.

Keywords: CD4+ T cells; CD8+ T cells; COVID-19; MIS-C; SARS-CoV-2; cellular immune responses.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Children with MIS show enhanced frequencies of SARS-CoV-2-specific CD4+ Th1 and Th17 cells. The net frequencies of Th1 and Th17 cytokines by CD4+ T cells with or without SARS-CoV-2-antigenic stimulation were compared statistically among MIS-C, children with COVID-19, and other infectious diseases. (A) CD4+ T cells at baseline or no stimulation; (B) CD4+ T cells at SARS-CoV S-RBD stimulation; (C) CD4+ T cells at SARS-CoV ICL stimulation; and (D) CD4+ T cells at M.tb WCL stimulation. Each circle in the scatter plot represents a single variable from an individual and the line at the center of the scatter plot is the geometric mean. The p-values were calculated using the Kruskal–Wallis test to show the significance and were represented as *, **, ***, and ****.
Figure 2
Figure 2
Children with MIS show enhanced frequencies of SARS-CoV-2-specific CD8+ Tc1 and Tc17 cells. The net frequencies of Tc1 and Tc17 cytokines by CD8+ T cells with or without SARS-CoV-2-antigenic stimulation were compared statistically among children with MIS, COVID-19, and other infectious diseases. (A) CD8+ T cells at baseline or no stimulation; (B) CD8+ T cells at SARS-CoV S-RBD stimulation; (C) CD8+ T cells at SARS-CoV ICL stimulation; and (D) CD8+ T cells at M.tb WCL stimulation. Each circle in the scatter plot represents a single variable from an individual and the line at the center of the scatter plot is the geometric mean. The p-values were calculated using the Kruskal–Wallis test to show the significance and were represented as *, **, ***, and ****.
Figure 3
Figure 3
A signature profile of CD4+ T. (A) Cells expressing Th1/17 cytokines and CD8+ T. (B) Cells expressing Tc1/17 cytokines upon SARS-CoV-2-specific antigen stimulation in MIS-C, children with COVID-19, and children with other infectious diseases.
Figure 4
Figure 4
(A) Children with MIS show diminished frequencies of SARS-CoV-2-specific CD4+ Th1 and Th17 cells after treatment. The net frequencies of Th1 and Th17 cytokines by CD4+ T cells with or without SARS-CoV-2 antigenic stimulation were compared statistically between pre- and post-treatment of MIS-C. (Top) CD4+ T cells at baseline or no stimulation; (Middle) CD4+ T cells at SARS-CoV S-RBD stimulation; and (Bottom) CD4+ T cells at SARS-CoV ICL stimulation. Each circle in the scatter plot represents a single variable from an individual and the line connecting to the circle of the same individual from pre- to post-treatment. The p-values were calculated using the Wilcoxon test for matched pairs. (B) Children with MIS show diminished frequencies of SARS-CoV-2-specific CD8+ Tc1 and Tc17 cells after treatment. The net frequencies of Tc1 and Tc17 cytokines by CD8+ T cells with or without SARS-CoV-2 antigenic stimulation were compared statistically between pre- and post-treatment of MIS-C. (Top) CD8+ T cells at baseline or no stimulation; (Middle) CD8+ T cells at SARS-CoV S-RBD stimulation; and (Bottom) CD8+ T cells at SARS-CoV ICL stimulation. Each circle in the scatter plot represents a single variable from an individual and the line connecting to the circle of the same individual from pre- to post-treatment. The p-values were calculated using Wilcoxon test for matched pairs.
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