Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance

Qingyong Xu, Junglim Lee, Ewa Jankowska-Gan, Jackie Schultz, Drew A. Roennburg, Lynn D. Haynes, Satoshi Kusaka, Hans W. Sollinger, Stuart J. Knechtle, Anne M. VanBuskirk, Jose R. Torrealba, William J. Burlingham

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Abstract

Adaptive T regulatory (TR) 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-β1 Ab revealed a response to immunodominant allopeptides in both patients, suggesting that CD4+ T elector (TE) cells coexisted with suppressive, TGF-β1-producing CD4+ TR cells. During in vitro culture, allopeptide stimulation induced both IFN-γ-producing and surface TGF-β1+ 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-β1 expression was found primarily in Forkhead box P3 (FoxP3)-negative CD4 +CD25low T cells, which could adoptively transfer suppression of donor-specific DTH. Biopsy samples contained numerous surface TGF-β1+ mononuclear cells that costained for CD4 and, less frequently CD25, but were negative for FoxP3. The CD4+TGF- β1+ T cells were localized primarily to the tubulointerstitium, whereas TGF-β1-FoxP3+CD25+ cells were found mainly in lymphoid aggregates. Thus, adaptive TR cells suppressing TE cell responses to donor allopeptides in two tolerant patients appear to be functionally and phenotypically distinct from CD4 +CD25highFoxP3+ T cells.

Original languageEnglish (US)
Pages (from-to)3983-3995
Number of pages13
JournalJournal of Immunology
Volume178
Issue number6
StatePublished - Mar 15 2007

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Delayed Hypersensitivity
Regulatory T-Lymphocytes
Transplants
Tissue Donors
T-Lymphocytes
Biopsy
HLA-B Antigens
SCID Mice
T-Lymphocyte Subsets
Kidney

ASJC Scopus subject areas

  • Immunology

Cite this

Xu, Q., Lee, J., Jankowska-Gan, E., Schultz, J., Roennburg, D. A., Haynes, L. D., ... Burlingham, W. J. (2007). Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance. Journal of Immunology, 178(6), 3983-3995.

Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance. / Xu, Qingyong; Lee, Junglim; Jankowska-Gan, Ewa; Schultz, Jackie; Roennburg, Drew A.; Haynes, Lynn D.; Kusaka, Satoshi; Sollinger, Hans W.; Knechtle, Stuart J.; VanBuskirk, Anne M.; Torrealba, Jose R.; Burlingham, William J.

In: Journal of Immunology, Vol. 178, No. 6, 15.03.2007, p. 3983-3995.

Research output: Contribution to journalArticle

Xu, Q, Lee, J, Jankowska-Gan, E, Schultz, J, Roennburg, DA, Haynes, LD, Kusaka, S, Sollinger, HW, Knechtle, SJ, VanBuskirk, AM, Torrealba, JR & Burlingham, WJ 2007, 'Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance', Journal of Immunology, vol. 178, no. 6, pp. 3983-3995.
Xu Q, Lee J, Jankowska-Gan E, Schultz J, Roennburg DA, Haynes LD et al. Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance. Journal of Immunology. 2007 Mar 15;178(6):3983-3995.
Xu, Qingyong ; Lee, Junglim ; Jankowska-Gan, Ewa ; Schultz, Jackie ; Roennburg, Drew A. ; Haynes, Lynn D. ; Kusaka, Satoshi ; Sollinger, Hans W. ; Knechtle, Stuart J. ; VanBuskirk, Anne M. ; Torrealba, Jose R. ; Burlingham, William J. / Human CD4+CD25low adaptive T regulatory cells suppress delayed-type hypersensitivity during transplant tolerance. In: Journal of Immunology. 2007 ; Vol. 178, No. 6. pp. 3983-3995.
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abstract = "Adaptive T regulatory (TR) 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-β1 Ab revealed a response to immunodominant allopeptides in both patients, suggesting that CD4+ T elector (TE) cells coexisted with suppressive, TGF-β1-producing CD4+ TR cells. During in vitro culture, allopeptide stimulation induced both IFN-γ-producing and surface TGF-β1+ 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-β1 expression was found primarily in Forkhead box P3 (FoxP3)-negative CD4 +CD25low T cells, which could adoptively transfer suppression of donor-specific DTH. Biopsy samples contained numerous surface TGF-β1+ mononuclear cells that costained for CD4 and, less frequently CD25, but were negative for FoxP3. The CD4+TGF- β1+ T cells were localized primarily to the tubulointerstitium, whereas TGF-β1-FoxP3+CD25+ cells were found mainly in lymphoid aggregates. Thus, adaptive TR cells suppressing TE cell responses to donor allopeptides in two tolerant patients appear to be functionally and phenotypically distinct from CD4 +CD25highFoxP3+ T cells.",
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AU - Haynes, Lynn D.

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