Extensive Amplification of Human Regulatory T Cells Alters Their Functional Capacities and Targets Them to the Periphery

Repetitive antigen encounters together with a strong CD28 co-stimulatory signal were recently identified as driving extensive amplification of human regulatory T (Treg) cells; however, the consequences of this on the functional capacities of Treg cells remain unknown. In this report, we reveal that T cell receptor (TCR)/CD28-triggered amplification in vitro converts CD4+CD25(high)FoxP3+ Treg cells into a late memory phenotype associated with immunosenescence and loss of CD7. Accordingly, ex vivo-isolated CD7- Treg cells have shortened telomeres and decreased telomerase expression compared to the majority of "mature" CD7+ Treg cells. Although they resist spontaneous apoptosis, amplified CD7- Treg cells exhibit increased sensitivity to activation-induced cell death (AICD). Extensive amplification of Treg cells is, moreover, accompanied by an increased activation threshold, reduced suppressor capacities, and interleukin-10 (IL-10) secretion, but secretion of high amounts of IL-4. Concomitantly, amplified Treg cells express homing receptors targeting them to the periphery. This is confirmed in vivo by the extensive accumulation of CD7- Treg cells with shortened telomeres in chronic inflammatory skin lesions, including atopic dermatitis and lichen ruber. Our data indicate that extensive amplification upon repetitive TCR/CD28 engagement alters the functional capacities of CD4+CD25(high) Treg cells toward less suppressive cells, but potential mediators in sustaining inflammatory reactions through IL-4.