Abstract
T lymphocytes elicit specific responses after recognizing cognate antigen. However, antigen-experienced T cells can also respond to non-cognate stimuli, such as cytokines. CD4+ Foxp3+ regulatory T cells (Treg) exhibit an antigen-experienced-like phenotype. Treg can regulate T cell responses in an antigen-specific or bystander way, and it is still unclear as to which extent they rely on T cell receptor (TCR) signals. The study of the antigen response of Treg has been hampered by the lack of downstream readouts for TCR stimuli. Here we assess the effects of TCR signals on the expression of a classical marker of early T cell activation, CD69. Although it can be induced following cytokine exposure, CD69 is commonly used as a readout for antigen response on T cells. We established that upon in vitro TCR stimulation CD69 induction on Foxp3+ Treg cells was more dependent on signaling via soluble factors than on TCR activation. By contrast, expression of the activation marker Nur77 was only induced after TCR stimulation. Our data suggest that Treg are more sensitive to TCR-independent signals than Foxp3- cells, which could contribute to their bystander activity.
Highlights
Foxp3-expressing regulatory T cells (Treg) are essential for establishing tolerance [1]
CD69 is expressed on all T cells upon T cell receptor (TCR) activation
While this may be a reasonable approach for the population of conventional Foxp3- T cells, it can be highly misleading when applied to Foxp3+ Treg, as many of these will increase CD69 expression in the absence of their cognate antigen
Summary
Foxp3-expressing regulatory T cells (Treg) are essential for establishing tolerance [1]. T cells are activated and maintained through TCR signals. While Treg can survive without TCR, they require TCR signals to become activated and to be able to fully mediate their suppressive function [2, 3]. TCR signals are necessary to suppress the activation of effector T cells with a different specificity in vitro (bystander suppression) [4, 5]. While several reports indicate that cognate antigen is required in vivo for Treg division and persistence under competitive settings [6, 7], it remains unclear whether Treg act in vivo in an antigen-specific manner or inhibit effector cells via bystander activity [8]. In vivo studies on Treg specificity have mostly been performed on TCR transgenic mice
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