Regulatory T cell expression of β1-integrin is critical to the maintenance of CD8+ T cell homeostasis and memory development in mice after infection.

Abstract

Abstract Regulatory T cells (Tregs) are recognized as suppressors of autoimmunity however; Tregs also play an important although variable role in the development of an immune response to infection. The mechanism of Treg modulation of and migration to immune activation sites during viral infections is not yet clearly defined. As such, we investigated the effect of Treg migratory protein expression on the development of an effective viral immune response. To test this hypothesis, we utilized an ITGb1Flox x FoxP3Cre conditional knockout mouse model. These mice generate Tregs that lack the ability to express β1-integrin, a transmembrane protein necessary for migration to sites of inflammation. Through flow cytometric analyses, we found that wild type (WT) Treg expression of β1-integrin correlated with an activated, migratory phenotype as indicated by increased surface expression of CD44, CXCR3, and CCR5. In addition, we found that when the balance of β1-integrin +/− Tregs is altered, the expression of suppressive proteins such as CD73 and CTLA4 is significantly decreased. Despite this potential loss in Treg functionality, there is no corresponding increase in mortality following primary infection. However, mice that received CD8+ T cells derived from previously infected β1-integrin Treg conditional knockouts succumbed to secondary infection at much greater rates than WT Treg recipients. This increase in mortality after secondary (but not primary) infection indicates that virus-specific memory CD8+ T cell development is compromised in β1-integrin conditional knockout mice. In sum, these data suggest that Treg migratory capability is critical for the maintenance and development of a functional CD8+ T cell response after infection.