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.
Rappl
Gunter
G
Tumorgenetics, Department of Internal Medicine I, University of Cologne, Cologne, Germany.
Schmidt
Annette
A
Mauch
Cornelia
C
Hombach
Andreas A
AA
Abken
Hinrich
H
D000328:Adult; D019011:Antigens, CD7 / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D016207:Cytokines / Q000096:biosynthesis; D003872:Dermatitis / Q000276:immunology / Q000473:pathology; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000502:physiology*; D055815:Young Adult
D019011:Antigens, CD7; D016207:Cytokines