Multiomic Immune Profiling of Pediatric Transplant Recipients Identifies Cell States Associated with Vaccine Response

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KEY POINTS: Pediatric transplant recipients have oligoclonal expansion of CD8 + T cells and polyclonal expansion of CD4 + T cells versus healthy children. Analysis of vaccine responses revealed patients with intact T cell immunity but impaired humoral immunity. A subset of pediatric transplant recipients exhibit an atypical B cell population previously associated with excessive immune activation. BACKGROUND: Immunosuppressive therapy after solid organ transplantation inhibits protective immunity to pathogens and vaccines. However, the specific cell states associated with failure to generate responsiveness to vaccination are not known. METHODS: We evaluated a broad spectrum of immune cell states in the peripheral blood of 12 pediatric solid organ transplant recipients (SOTRs) and eight healthy children immediately before receiving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, by performing single-cell RNA-sequencing, T cell receptor sequencing, and cytometry by time-of-flight. We then evaluated associations between the identified cell states and the development of anti-SARS-CoV-2 S-protein-specific antibody and CD4 + T cell activation after an initial series of SARS-CoV-2 vaccinations. RESULTS: We found clonal expansion of a subset of CD8 + effector T cells and a polyclonal expansion of CD4 + effector T cell populations in SOTRs compared with healthy controls. Responses to vaccination included normal SARS-CoV-2-specific T cell and antibody responses, intact T cell responses but impaired antibody responses, and absence of T cell and antibody responses. Comparison among the prevaccination cell states and responsiveness revealed a higher frequency of atypical B cells in SOTRs with intact T cell but impaired antibody responses compared with healthy controls. Also, T cell-only SOTR responders had lower numbers of immature γ δ T cells compared with SOTR nonresponders. By contrast, there was no definitive cell state that identified an absent immune response in SOTRs, but interactome analysis suggested that robust cellular interactions between myeloid, T cells, and B cells are required for successful responses to vaccination. CONCLUSIONS: Our findings in this exploratory observational study suggest that higher frequencies of atypical B cells in the peripheral blood of pediatric SOTRs may identify intact cellular but absent humoral responsiveness to vaccination. Intact T cell responsiveness to antigens may be sufficient to monitor protective immunity after vaccination in SOTRs.

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