NRP1 and CD73 expressing anergic CD4 T cells are progenitors for Foxp3 Treg cell differentiation in neonates

While the majority of self-reactive CD4⁺ T cells are deleted or become Foxp3⁺ regulatory T cells during thymic development, some self-reactive conventional Foxp3^– T cells escape to the secondary lymphoid organs early in life. The induction of anergy in such potentially autoreactive T cells has been proposed as one solution to maintaining tolerance to self-antigens; however, the data are lacking. We have addressed this knowledge gap by characterizing anergy development during the neonatal period. Anergy is shown here to be induced in self-reactive CD4⁺ T cells during the first 10 d of life in response to continuous antigen recognition, and such tolerant T cells are maintained for at least 80 d. Furthermore, NRP1 and CD73 are demonstrated to be reliable phenotypic markers for anergy development in the neonates. Finally, data indicate that conventional NRP1 and CD73 expressing anergic polyclonal CD4⁺ T cells are efficient progenitors for the peripheral transdifferentiation of Foxp3⁺ regulatory T cells during the neonatal period.