T Cell Receptor Sequencing Reveals Reduced Clonal Breadth of T Cell Responses against SARS-CoV-2 after Natural Infection and Vaccination in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is still associated with significant morbidity and mortality related to infectious complications, with viral infections being the most frequent infectious events. Allogenic HSCT recipients have a higher risk to develop severe forms of COVID-19 and a higher mortality rate after infection with SARS-CoV2 compared to the general population. Prevention by vaccination is critically important in allogeneic HSCT recipients but impaired humoral and cellular responses have been reported. To gain further insights into the immune defects leading to impaired immune responses to SARS-CoV-2 in allogeneic HSCT recipients we performed high-throughput T cell receptor (TCR) repertoire profiling of cells recovered from allogeneic HSCT recipients or healthy controls after SARS-CoV2 natural infection or mRNA-based vaccination. SARS-CoV-2- specific T cell clonotypes were detectable in both HC (n=10) and HSCT (n=11) recipients after COVID-19 infection. However, HSCT recipients displayed significantly reduced SARS-CoV-2-specific T cell clonotypes and a less diverse TCR repertoire, as revealed by higher Simpson clonality, compared with HC. Performing the same analysis on samples recovered from allogeneic HSCT recipients (n=11) or from healthy controls (n=10) after vaccination with 3 doses of mRNA-based SARS-CoV-2 vaccines, we observed a significant reduction in S-protein-specific T cell clonotypes in allogeneic HSCT recipient compared to HC. We detected a significant negative correlation between the Simpson clonality and the number of SARS-CoV-2-specific T cell clonotypes following natural infection or vaccination. Our results indicate that allogeneic HSCT recipients display a defect in cellular SARS-CoV-2-specific responses after COVID-19 infection and vaccination. Such impairment was associated with increased T-cell clonality after HSCT, pointing to the reduced diversity of the TCR repertoire as a mechanism leading to impaired cellular responses against SARS-CoV-2 in HSCT recipients. SARS-CoV-2 infection represents an unprecedented opportunity to study the immune responses established in allogeneic HSCT recipients against a new pathogen that either the donor or the HSCT recipient have never been exposed to. Our findings provide insights into our understanding of immune-dysfunction after allogeneic HSCT.