The emergence of purinergic signaling has given ATP and other extracellular nucleotides a whole new perspective. This concept refers to the fact that extracellular nucleotides released by most cells act as signaling molecules via specific membrane receptors called purinergic receptors, thus regulating several cellular functions. Although purinergic signaling has been well studied in several physiological systems, recent work has shown that this signaling pathway is also essential in the immune system. In this review, we will discuss the complex role of purinergic signaling in the regulation of effector T cell functions, including migration, differentiation, and activation. We will also cover the role of P2 receptors in the development of autoimmune diseases. Understanding how P2 receptors regulate effector T cells will likely further our understanding of protective immunity and immune pathogenesis and may lead to new therapeutic approaches and agents in immune diseases

The emergence of purinergic signaling has given ATP and extracellular nucleotides a whole new perspective. This concept refers to the fact that extracellular nucleotides released by most cells act as signaling molecules via specific membrane receptors called purinergic receptors, thus regulating several cellular functions. Although purinergic signaling has been well studied in several physiological systems, recent work has shown that this signaling pathway is also essential in the immune system. In this minireview, we will discuss the complex role of purinergic signaling in the regulation of effector T cell functions, including migration, differentiation, and activation. We will also cover the role of P2 receptors in the development of autoimmune diseases. Un-derstanding how P2 receptors regulate effector T cells will likely further our under-standing of protective immunity and immune pathogenesis and may lead to new therapeutic approaches and agents in immune diseases

Th17 cells play an important role in adaptive immunity and inflammation; however, the mechanisms regulating their migration into inflammatory tissues are not fully understood. In this study, we found that ex vivo human effector/memory but not central/memory Th17 cells express and use the discoïdin domain receptor 1 (DDR1) to migrate in collagen gels. The tyrosine kinase activity of DDR1 is essential to this process since its blockade with the DDR1 kinase inhibitor 7rh and the DDR1 kinase-dead construct inhibited the migration of human Th17 cells. Our results indicated that the DDR1 kinase activity enhanced Th17 cell migration by activating the MAPK/ERK pathway. We then examined the role of DDR1 in the inflammatory model of collagen-induced arthritis (CIA). Treatment of CIA mice with the DDR1 kinase inhibitor 7rh led to reduced arthritis severity, synovial inflammation and cartilage destruction. DDR1 expression is higher on T cells isolated from CIA mice than on those from naïve mice, and its blockade inhibited Th17 cell infiltration into the joints, which was associated with the inhibition of IL-17 levels. Along these lines, isolated T cells from 7rh-treated arthritic mice showed a drastic reduction in migration in collagen gels compared to those isolated from control arthritic mice. Further, the 7rh treatment reduced the levels of TNF-α and IL-1β and increased the levels of IL-10, thus promoting an anti-inflammatory environment. Our findings provide an important role for the DDR1 tyrosine kinase in promoting Th17 cell infiltration into inflammatory tissues, especially in collagen-rich tissues like the joints, and in the development of arthritis.