Chronic infection control relies on T cells with lower foreign antigen binding strength generated by N-nucleotide diversity

Jamaleddine, H.; Rogers, D.; Perreault, G.; Mandl, J. N.; Khadra, A.

doi:10.1101/2022.06.26.497644

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bioRxiv · 10.1101/2022.06.26.497644

Chronic infection control relies on T cells with lower foreign antigen binding strength generated by N-nucleotide diversity

Jamaleddine, H.·Rogers, D.·Perreault, G.·Mandl, J. N.·Khadra, A.

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Abstract

The pathogens to which T cells respond is determined by the T cell receptors (TCRs) present in an individuals repertoire. Although more than 90% of the TCR repertoire is generated by terminal deoxynucleotidyl transferase (TdT)-mediated N-nucleotide addition during V(D)J recombination, the benefit of TdT-modified TCRs remains unclear. Here, we computationally and experimentally investigated whether TdT systematically modifies the affinity distribution of a TCR repertoire in ways that impacts acute or chronic infection. Our computational model predicts a shift toward low-affinity T cells over time during chronic, but not acute, infections. Elimination of low-affinity T cells in silico substantially delayed chronic infection clearance. Corroborating an affinity-centric benefit for TCR diversity, we showed that infection of TdT-deficient mice delayed the clearance of a chronic viral pathogen, while acute viral control was unaffected. Our data thus suggest that TdT-mediated TCR diversity is of particular benefit in the control of prolonged pathogen replication.

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Jamaleddine, H., Rogers, D., Perreault, G., Mandl, J. N., Khadra, A.. 2022-06-28. Chronic infection control relies on T cells with lower foreign antigen binding strength generated by N-nucleotide diversity. https://doi.org/10.1101/2022.06.26.497644

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