Natural Foxp3+ regulatory T cells (Treg) are of paramount importance for establishing self-tolerance, controlling inflammatory responses and maintaining immune homeostasis. The identification of new molecules controlling Treg functions is nowadays an important challenge. We previously reported the implication of Themis, a new actor of TCR signaling, in Treg suppressive capacities. Indeed, Treg from Themis deficient BN rats were defective, leading to the development of an inflammatory bowel disease. In the present study, we show that Themis deficiency does not impair Treg suppressive functions and does not induce any pathological manifestations in LEW rats. These findings suggest that an interaction with other(s) gene(s) may contribute to the Treg defect and disease development in Themis deficient BN rats. To test this hypothesis and identify the involved gene(s), we performed a genetic dissection using different congenic lines. We show that the impact of Themis deficiency on Treg suppressive functions requires the expression of a constitutively active Vav1 variant. Together, these studies highlight the importance of Vav1 and Themis signaling hub in regulating the suppressive functions of Treg. Understanding the underlying molecular mechanisms may lead to advances in Treg biology and favor the identification of new pharmacogenetic markers and therapeutic targets in immune mediated diseases.
- Copyright © 2013 by The American Association of Immunologists, Inc.