Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation.
T-cell dysfunction after human hematopoietic stem-cell transplantation (HSCT) is generally attributed to intrinsic T-cell defects. Here we show that the characteristic impaired proliferative responses to polyclonal stimulation of post-HSCT peripheral blood mononuclear cells (PB-MCs) were markedly (4-fold) improved by T-cell enrichment. Conversely, addback of post-HSCT monocytes to these enriched T cells dampened their proliferative responses, suggesting that post-HSCT monocytes effectively mediate T-cell suppression. As a mechanism possibly contributing to monocyte-mediated T-cell suppression, we investigated monocyte tryptophan catabolism by indoleamine 2,3-dioxygenase into kynurenine, which has been implicated in regulating T-cell responses. Compared with controls, all post-HSCT monocyte-containing cell cultures (total PBMCs, monocytes, and monocyte/T-cell cocultures), but not monocyte-depleted populations, secreted elevated amounts of kynurenine. Blockade of tryptophan catabolism improved the proliferative responses. The slightly increased kynurenine release and substantial release of neopterin by unstimulated post-HSCT monocytes suggests that they were in a state of continuous activation. Superimposed on this state, stimulation of these cells caused a striking, additional increase (10-fold) in kynurenine release, and they triggered marked apoptosis of autologous post-HSCT T cells. We conclude that the amplified kynurenine release by post-HSCT monocytes, particularly induced upon stimulation, may underlie their suppressor activity, which in turn may contribute to the depressed T-cell immune responses after HSCT.
Hainz
Ursula
U
Children's Cancer Research Institute, St Anna Children's Hospital, Kinderspitalgasse 6, A-1090 Vienna, Austria.
Obexer
Petra
P
Winkler
Christiana
C
Sedlmayr
Peter
P
Takikawa
Osamu
O
Greinix
Hildegard
H
Lawitschka
Anita
A
Pötschger
Ulrike
U
Fuchs
Dietmar
D
Ladisch
Stephan
S
Heitger
Andreas
A
D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007737:Kynurenine / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism* / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D007737:Kynurenine; D014364:Tryptophan; D014366:Tryptophan Oxygenase