Abstract
Type 1 regulatory CD4+ T (Tr1) cells express high levels of the immunosuppressive cytokine IL-10 but not the master transcription factor Foxp3, and can suppress inflammation and promote immune tolerance. In order to identify and obtain viable Tr1 cells for research and clinical applications, co-expression of CD49b and LAG3 has been proposed as a unique surface signature for both human and mouse Tr1 cells. However, recent studies have revealed that this pattern of co-expression is dependent on the stimulating conditions and the differentiation stage of the CD4+ T cells. Here, using an IL-10GFP/Foxp3RFP dual reporter transgenic murine model, we demonstrate that co-expression of CD49b and LAG3 is not restricted to the Foxp3− Tr1 cells, but is also observed in Foxp3+ T regulatory (Treg) cells and CD8+ T cells that produce IL-10. Our data indicate that IL-10-producing Tr1 cells, Treg cells and CD8+ T cells are all capable of co-expressing LAG3 and CD49b in vitro following differentiation under IL-10-inducing conditions, and in vivo following pathogenic insult or infection in the pulmonary mucosa. Our findings urge caution in the use of LAG3/CD49b co-expression as sole markers to identify Tr1 cells, since it may mark IL-10-producing T cell lineages more broadly, including the Foxp3− Tr1 cells, Foxp3+ Treg cells, and CD8+ T cells.
Highlights
The mammalian immune system has evolved both effector and regulatory immune axes to protect the host from invading pathogens, along with a control mechanism to tune the level of immune reactivity against self- and non-self- agents to prevent host tissue damage
LAG3 and CD49b co-expression was previously reported to be a cell surface signature for both mouse and human IL10-producing CD4+ T cells that lack the expression of Foxp3 [15]
We and others have previously reported that co-culturing murine naïve CD4+ T cells with antigen presenting cells (APCs) in the presence of anti-CD3, anti-CD28, anti-IFN-γ, anti-IL-12, and IL-27 can efficiently induce the differentiation of Tr1 cells [28, 40, 43], which express high levels of LAG3 and CD49b
Summary
The mammalian immune system has evolved both effector and regulatory immune axes to protect the host from invading pathogens, along with a control mechanism to tune the level of immune reactivity against self- and non-self- agents to prevent host tissue damage. Interleukin-10 (IL-10) is a regulatory cytokine with a demonstrated anti-inflammatory function and plays an essential role in preventing allergic inflammation [1], autoimmunity [2], and pathogen-induced immunopathology [3, 4], but can promote the establishment and maintenance of chronic infection [5, 6]. Regulatory T cells are defined by their immunosuppressive function, and the three aforementioned subsets of IL-10-producing T cells have been reported as phenotypically distinct regulatory T cell subsets, playing important roles in promoting immune tolerance and/or suppressing inflammation in both mouse and human [15,16,17,18,19,20]
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