Human regulatory T cell suppressive function is independent of apoptosis induction in activated effector T cells.
BACKGROUND
CD4(+)CD25(+)FOXP3(+) Regulatory T cells (Treg) play a central role in the immune balance to prevent autoimmune disease. One outstanding question is how Tregs suppress effector immune responses in human. Experiments in mice demonstrated that Treg restrict effector T cell (Teff) responses by deprivation of the growth factor IL-2 through Treg consumption, resulting in apoptosis of Teff.


RESULTS
In this study we investigated the relevance of Teff apoptosis induction to human Treg function. To this end, we studied naturally occurring Treg (nTreg) from peripheral blood of healthy donors, and, to investigate Treg function in inflammation in vivo, Treg from synovial fluid of Juvenile Idiopathic Arthritis (JIA) patients (SF-Treg). Both nTreg and SF-Treg suppress Teff proliferation and cytokine production efficiently as predicted. However, in contrast with murine Treg, neither nTreg nor SF-Treg induce apoptosis in Teff. Furthermore, exogenously supplied IL-2 and IL-7 reverse suppression, but do not influence apoptosis of Teff.


CONCLUSIONS
Our functional data here support that Treg are excellent clinical targets to counteract autoimmune diseases. For optimal functional outcome in human clinical trials, future work should focus on the ability of Treg to suppress proliferation and cytokine production of Teff, rather than induction of Teff apoptosis.
Department of Pediatric Immunology, Center for Molecular and Cellular Intervention, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. y.vercoulen@umcutrecht.nl
Yvonne
Y
Vercoulen
Ellen J
EJ
Wehrens
Nienke H
NH
van Teijlingen
Wilco
W
de Jager
Jeffrey M
JM
Beekman
Berent J
BJ
Prakken
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007107:Immune System; D007249:Inflammation; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis*; D015851:Interleukin-7 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015851:Interleukin-7