Distinct characteristics of T cell receptor repertoire associated with the SARS-CoV-2 reinfection

Liling Zeng¹Li Liu²Baolin Ren¹Bing Feng¹Xudong Lai²Xunxi Lai²Zhimin Chen^3*Yihui Huang^4*Wenxin Hong^4*

• ¹The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
• ²Guangzhou Red Cross Hospital, Guangzhou, China
• ³Guangdong Polytechnic Normal University, Guangzhou, China
• ⁴Eighth People's Hospital of Guangzhou, Guangzhou, China

The COVID-19 pandemic, caused by SARS-CoV-2, represents one of the most profound global public health challenges in modern history. While T cell immunity is crucial for viral clearance, the dynamics of the T cell receptor (TCR) repertoire during reinfection remain poorly understood. This study sought to characterize the TCR repertoire in peripheral blood T cells from healthy convalescent individuals (HC), patients with primary SARS-CoV-2 infection (PI), and reinfected individuals (RI), aiming to identify distinct TCR signatures linked to susceptibility or protection against reinfection. We enrolled 48 age-and sex-matched participants (18 PI, 18 RI, 12 HC), collecting blood samples during acute infection (PI/RI) or convalescence (HC). Deep TCRα/β sequencing was performed using the SMARTer Human TCR Profiling Kit with unique molecular identifiers (UMIs), followed by analysis of TCR repertoire diversity, clonal expansion, V(D)J gene usage, and CDR3 characteristics. Compared to HC, both PI and RI groups exhibited significantly reduced TCR diversity (p< 0.001), though no significant differences were observed between PI and RI. COVID-19 patients displayed skewed TCR repertoires dominated by expanded clones (>1%), whereas HC primarily harbored small clones (≤ 0.1%). RI patients demonstrated intermediate clonality, suggesting partial memory recall. Group-specific V(D)J pairings were identified, including TRAV27/TRAJ42 in RI, TRAV24/TRAJ42 in PI, and TRAV35/TRAJ42 in HC, while TRBV6-4/TRBD2/TRBJ2-3 was conserved across all groups. Additionally, HC-enriched and RI-exclusive CDR3 clusters were detected. Our findings indicate that SARS-CoV-2 reinfection is associated with impaired TCR diversity and distinct clonal expansion patterns, underscoring the role of T cell immunity in reinfection susceptibility. HC-enriched TCR clusters may represent protective memory responses, whereas RI-specific signatures suggest compromised immunity. These results offer valuable insights for vaccine design and risk stratification, though further functional validation of the identified TCRs is necessary.