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Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection.

Kilian Schober¹, Florian Voit², Simon Grassmann²

¹Institute for Medical Microbiology, Immunology and Hygiene, Technische Universität München (TUM), Munich, Germany. kilian.schober@tum.de.

Nature Immunology

|March 25, 2020

Summary

During chronic infections, T cell receptor (TCR) affinity maturation shifts. High-affinity TCRs decline, while low-affinity TCRs expand, impacting immune responses and therapies.

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Area of Science:

Immunology
T cell biology
Adaptive immunity

Background:

T cell receptor (TCR) affinity is crucial for adaptive immunity.
High-affinity TCRs typically dominate acute immune responses.
The evolution of TCR repertoire affinity during chronic infections is not fully understood.

Purpose of the Study:

To investigate the changes in TCR repertoire and affinity during chronic cytomegalovirus (CMV) infection.
To determine if affinity maturation by clonal selection persists in chronic infections.

Main Methods:

Single-cell and bulk TCR sequencing in human and mouse models.
Structural affinity analyses of CMV-specific T cells.
In vivo monitoring of defined TCR repertoires.

Main Results:

The immunodominance of high-affinity TCRs decreased during chronic CMV infection.
Cellular senescence is a likely cause for the decline in high-affinity clones.
Low-affinity TCRs showed preferential expansion in the TCR repertoire under chronic antigen exposure.

Conclusions:

TCR repertoire evolution during chronic infection favors low-affinity receptors.
This shift has significant implications for developing effective immunotherapeutic strategies for chronic diseases.