Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance.
Adaptive T regulatory (T(R)) cells mediate the suppression of donor-specific, delayed-type hypersensitivity (DTH) in tolerant organ transplant recipients. We hypothesized that cells belonging to the CD4(+)CD25(+) T cell subset but distinct from natural T(R) cells may fulfill this role. To test this hypothesis, PBMC and biopsy samples from two tolerant kidney transplant recipients (K1 and K2) were analyzed. When transferred with recipient APC into a SCID mouse footpad, CD4(+) T cells were hyporesponsive in DTH to donor type HLA-B Ags and derivative allopeptides. However, anti-human TGF-beta1 Ab revealed a response to immunodominant allopeptides in both patients, suggesting that CD4(+) T effector (T(E)) cells coexisted with suppressive, TGF-beta1-producing CD4(+) T(R) cells. During in vitro culture, allopeptide stimulation induced both IFN-gamma-producing and surface TGF-beta1(+) T cells. The relative strength of the latter response in patient K1 was inversely correlated with the level of systemic anti-donor DTH, which varied over a 6-year interval. Allopeptide-induced surface TGF-beta1 expression was found primarily in Forkhead box P3 (FoxP3)-negative CD4(+)CD25(low) T cells, which could adoptively transfer suppression of donor-specific DTH. Biopsy samples contained numerous surface TGF-beta1(+) mononuclear cells that costained for CD4 and, less frequently CD25, but were negative for FoxP3. The CD4(+)TGF-beta1(+) T cells were localized primarily to the tubulointerstitium, whereas TGF-beta1(-)FoxP3(+)CD25(+) cells were found mainly in lymphoid aggregates. Thus, adaptive T(R) cells suppressing T(E) cell responses to donor allopeptides in two tolerant patients appear to be functionally and phenotypically distinct from CD4(+)CD25(high)FoxP3(+) T cells.
Xu
Qingyong
Q
Department of Surgery, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA.
Lee
Junglim
J
Jankowska-Gan
Ewa
E
Schultz
Jackie
J
Roenneburg
Drew A
DA
Roennburg
Drew A
DA
Haynes
Lynn D
LD
Kusaka
Satoshi
S
Sollinger
Hans W
HW
Knechtle
Stuart J
SJ
VanBuskirk
Anne M
AM
Torrealba
Jose R
JR
Burlingham
William J
WJ
D019264:Adoptive Transfer; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000637:transplantation; D051858:Forkhead Transcription Factors / Q000276:immunology; D015235:HLA-B Antigens / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D010455:Peptides / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D014019:Tissue Donors; D053773:Transforming Growth Factor beta1 / Q000276:immunology; D023001:Transplantation Tolerance; D014183:Transplantation, Heterologous; D014184:Transplantation, Homologous
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015235:HLA-B Antigens; D007519:Isoantigens; D010455:Peptides; D053773:Transforming Growth Factor beta1