Monday, October 27, 2025

Front. Immunol.: Distinct Characteristics of T cell Receptor Repertoire Associated with the SARS-CoV-2 Reinfection

 

#18,925

While most people now trivialize COVID infection as little more than a `bad cold' - and COVID vaccine uptake has dropped precipitously - at the same time we've seen consistent and compelling evidence that repeated SARS-CoV-2 infections can lead to `Long COVID' and other sequalae. 

Most people with Long COVID experience symptoms days after first learning they had COVID-19, but some people who later develop Long COVID do not know when they were infected. People can be reinfected with SARS-CoV-2 multiple times. 
Each time a person is infected with SARS-CoV-2, they have a risk of developing Long COVID.  Long COVID symptoms and conditions can emerge, persist, resolve, and reemerge over weeks and months. These symptoms and conditions can range from mild to severe, may require comprehensive care, and can even result in a disability.
Like it or not, there is evidence that COVID remains more than just a garden-variety respiratory virus. Elevated rates of hypertension, diabetes, and stroke have all been reported following COVID infection. 

Less clear are (often anecdotal) reports of increased susceptibility to viral or bacterial infections, particularly after repeated COVID infections.   

Today we've a report, published last week in Frontiers in Immunology, which finds (among a relatively small, single-center study) that people who contract COVID-19 more than once have reduced diversity in their T cell receptors, which are crucial for fighting infections. 

They compared blood samples from 48 individuals aged 20–40 across three cohorts (18 Primary Infection, 18 Reinfections, and 12 Healthy Controls), and found distinct differences in T Cell populations.

This study is causing quite a stir online, but the authors caution that these findings are correlative, and do not establish whether these observed immune changes are the primary drivers of post-infection sequalae. 

This is, as you might imagine, a highly detailed and technical report, and I'll leave it to others far more qualified than I to opine further.  I've reproduced the Abstract, and a few brief excerpts below.  

Follow the link to read it in its entirety.  I'll have a brief postscript after you return. 

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

Liling Zeng , Li Liu , Baolin Ren , Bing Feng , Xudong Lai, Xunxi Lai, Zhimin Chen , Yihui Huang, Wenxin Hong 
Abstract

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.

        (SNIP)

Our study reveals distinct TCR repertoire signatures associated with SARS-CoV-2 reinfection, characterized by reduced clonal diversity, antigen-driven expansion, cohort-specific V(D)J recombination patterns, and exclusive CDR3 AA sequence clusters.
The HC-enriched TCR clusters likely represent protective memory T-cell populations, whereas the PI/RI groups exhibited repertoire dynamics consistent with antigen-specific selection pressure.
Notably, the significant divergence between RI and HC repertoires suggests compromised T-cell immunity in reinfected individuals, potentially explaining their susceptibility to recurrent infection. We suppose that these TCR sequences represent clonotype subsets that confer SARS-CoV-2 immunity, and that their depletion or dysregulation may contribute to the pathogenesis of reinfection. This interpretation is consistent with other viral models, such as influenza, in which T-cell-mediated immunity has been shown to play a critical role in protection against reinfection (39, 40). These findings advance our mechanistic understanding of recall T-cell responses in reinfection and inform rational vaccine design and immunotherapeutic strategies.

While this study enhances our understanding of T-cell responses in reinfection, several limitations should be noted. First, as a curated database, VDJdb is subject to coverage bias and may overrepresent certain epitopes while underrepresenting others. Second, TCR specificity inferences rely on sequence similarity and previously reported associations in VDJdb and have not been experimentally validated in our cohort. Furthermore, functional assays, such as TCR specificity testing and epitope mapping, are needed to confirm the protective role of the identified T-cell clusters and to elucidate the mechanistic basis of their effects.

        (Continue . . . )


While I risk getting another warning letter from the ASPCA for continuing to beat a dead horse, this is probably the 100th study we've looked at that has found credible evidence of long-term damage from COVID infection. 

A few recent examples include:


Which is why I got both my updated COVID and seasonal flu shot from my local pharmacist a couple of weeks ago, and I continue to wear a (KN95) face mask in crowded indoor environments. 

While these precautions may not be 100% protective - they can go a long way toward reducing my risks of infection. 

And given my age - and my limited number of functioning neurons - it seems like cheap insurance to me. 
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