Tcf1+ cells are required to maintain the inflationary T cell pool upon MCMV infection

Suzanne P M Welten,Jennifer D Oduro,Alessandro Pedrioli,Annette Oxenius,Sai T Reddy,Ioana Sandu,Luka Cicin-Sain,Nathalie Oetiker,Alexander Yermanos,Franziska Wagen,Nicolas S Baumann,Werner Held

doi:10.1038/s41467-020-16219-3

Suzanne P M Welten, Jennifer D Oduro + Show 10 more

Open Access

https://doi.org/10.1038/s41467-020-16219-3

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Abstract

Cytomegalovirus-based vaccine vectors offer interesting opportunities for T cell-based vaccination purposes as CMV infection induces large numbers of functional effector-like cells that accumulate in peripheral tissues, a process termed memory inflation. Maintenance of high numbers of peripheral CD8 T cells requires continuous replenishment of the inflationary T cell pool. Here, we show that the inflationary T cell population contains a small subset of cells expressing the transcription factor Tcf1. These Tcf1+ cells resemble central memory T cells and are proliferation competent. Upon sensing viral reactivation events, Tcf1+ cells feed into the pool of peripheral Tcf1− cells and depletion of Tcf1+ cells hampers memory inflation. TCR repertoires of Tcf1+ and Tcf1− populations largely overlap, with the Tcf1+ population showing higher clonal diversity. These data show that Tcf1+ cells are necessary for sustaining the inflationary T cell response, and upholding this subset is likely critical for the success of CMV-based vaccination approaches.

Highlights

Cytomegalovirus-based vaccine vectors offer interesting opportunities for T cell-based vaccination purposes as CMV infection induces large numbers of functional effector-like cells that accumulate in peripheral tissues, a process termed memory inflation
There are CMV-specific T cells that follow the classical pattern of expansion, contraction and formation of long-term central memory pools (TCM: CD62L+/CD127+/KLRG1−/CD27+), during viral latency the immune response is dominated by inflationary T cell responses that are restricted to a few epitopes[5]
We found that a small subset of inflationary T cells, enriched in lymph nodes (LNs), expresses Tcf[1]

Summary

Introduction

Cytomegalovirus-based vaccine vectors offer interesting opportunities for T cell-based vaccination purposes as CMV infection induces large numbers of functional effector-like cells that accumulate in peripheral tissues, a process termed memory inflation. TCR repertoires of Tcf1+ and Tcf1− populations largely overlap, with the Tcf1+ population showing higher clonal diversity These data show that Tcf1+ cells are necessary for sustaining the inflationary T cell response, and upholding this subset is likely critical for the success of CMV-based vaccination approaches. There are CMV-specific T cells that follow the classical pattern of expansion, contraction and formation of long-term central memory pools (TCM: CD62L+/CD127+/KLRG1−/CD27+), during viral latency the immune response is dominated by inflationary T cell responses that are restricted to a few epitopes[5]. These cells have an activated effector memory/effector-like phenotype (TEM: CD62L−/CD127−/KLRG1+/CD27low), suggestive of repetitive antigen encounter. While active viral replication is generally not measurable during viral latency, viral peptides that are processed by the constitutive proteasome[6,7] are likely present and are presented by latently infected non-hematopoietic cells[8,9]

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