Impact of the TCR Signal on Regulatory T Cell Homeostasis, Function, and Trafficking

Joong Kyu Kim,Yuanyuan Xiao,Mark Klinger,Dan R Littman,Jonathan Benjamin,Nigel Killeen,David J Erle,Derya Unutmaz

doi:10.1371/journal.pone.0006580

Joong Kyu Kim, Yuanyuan Xiao + Show 6 more

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https://doi.org/10.1371/journal.pone.0006580

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Abstract

Signaling through the T cell antigen receptor (TCR) is important for the homeostasis of naïve and memory CD4+ T cells. The significance of TCR signaling in regulatory T (Treg) cells has not been systematically addressed. Using an Ox40-cre allele that is prominently expressed in Treg cells, and a conditional null allele of the gene encoding p56Lck, we have examined the importance of TCR signaling in Treg cells. Inactivation of p56Lck resulted in abnormal Treg homeostasis characterized by impaired turnover, preferential redistribution to the lymph nodes, loss of suppressive function, and striking changes in gene expression. Abnormal Treg cell homeostasis and function did not reflect the involvement of p56Lck in CD4 function because these effects were not observed when CD4 expression was inactivated by Ox40-cre.The results make clear multiple aspects of Treg cell homeostasis and phenotype that are dependent on a sustained capacity to signal through the TCR.

Highlights

Regulatory T cells (Treg cells) are defined by expression of the Forkhead transcription factor FoxP3 and by potent immunosuppressive capability [1,2,3,4]
Expression of Ox40-cre in Regulatory T Cells Ox40-cre is an allele of the Ox40 gene that expresses the Cre recombinase in place of OX40 [25]
To determine which cells undergo Cre recombination in Ox40-cre mice, we crossed them to mice carrying a Cre-activated ROSA26-YFP reporter allele [26]. 98% of peripheral T cells that had undergone recombination and become YFP+ in such mice were CD4+ (Figure 1A), and among these one-third to one-half were FoxP3+ depending on age at the time of analysis

Summary

Introduction

Regulatory T cells (Treg cells) are defined by expression of the Forkhead transcription factor FoxP3 and by potent immunosuppressive capability [1,2,3,4]. These cells develop in the thymus through a CD25hiCD4+CD82 intermediate in a process that depends on the cc cytokines IL-2, -7 or -15 [5,6,7]. There have, been conflicting observations about this [22,23] While it has not been systematically addressed, there are indications that like memory CD8+ T cells, Treg cell homeostasis is minimally influenced by TCR signaling [24]

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