Regulatory functions of human CD4+ T cells recognizing allopeptides in the context of self-HLA class II

Roelen, Dave L.; Bree, Simone van; Hulst, Paula van; Beelen, Els van; Claas, Frans H.J.

doi:10.1016/s0198-8859(02)00453-6

Cited by 16 publications

(10 citation statements)

References 40 publications

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“…The class II restriction element for p37-MA in patient K2 is less clear. A degree of promiscuity in peptide binding and recognition was previously suggested for CD4 indirect pathway T cells cloned from a transplant nephrectomy (46), one of which was inducible for surface TGF-␤1 and had the functional characteristics of an adaptive T R cell (47).…”

Section: Foxp3mentioning

confidence: 84%

Human CD4+CD25low Adaptive T Regulatory Cells Suppress Delayed-Type Hypersensitivity during Transplant Tolerance

Lee

Jankowska‐Gan

et al. 2007

The Journal of Immunology

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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 TR 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 effector (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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Section: Foxp3mentioning

confidence: 84%

Human CD4+CD25low Adaptive T Regulatory Cells Suppress Delayed-Type Hypersensitivity during Transplant Tolerance

Lee

Jankowska‐Gan

et al. 2007

The Journal of Immunology

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“…[6][7][8] However, other studies have pointed to a protective role of alloreactive CD4 ϩ T cells, which are able to mediate immunologic tolerance to the graft. 9,10 Visualization and characterization of alloreactive CD4 ϩ T cells is necessary to elucidate the role of these cells in rejection or tolerance of the transplanted organ in humans. However, currently there are no assays available that can identify alloreactive CD4 ϩ T cells on the single-cell level without prior long-term culture.…”

Section: Introductionmentioning

confidence: 99%

The human alloreactive CD4+ T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches

Litjens¹,

Wetering²,

Besouw

et al. 2009

Blood

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“…5 & [21]), which happens when the MHC class I is mismatched and class II is identical or closely matched between the organ donor and recipient. Clone EL26 [9, 10] would be another example of this unusual type of alloreactivity. As shown in Figure 5, such CD4 T cells can recognize both the direct native presentation of the mismatched MHC class I antigen-derived allopeptide by donor antigen presenting cells (APC), as well as the indirect presentation of the same class I allopeptide by recipient APC that ingest soluble donor HLA class I.…”

Section: Discussionmentioning

confidence: 99%

“…The HLA-A2-mismatched donor expressed a different DR2 subtype (DRB1*1501), yet the naturally processed and presented A2 peptide was recognized by one of the T cell clones, named EL26 [9], a CD4 + . EL26 was later found to be a CD25 + CTLA-4 (surface) + TGF-β (surface) + adaptive T regulatory cell [10]. …”

Section: Introductionmentioning

confidence: 99%

Analysis of indirect pathway CD4+ T cells in a patient with metastable tolerance to a kidney allograft

Lee

Keller

et al. 2009

Transplant Immunology

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MHC class I mismatched, but class II matched kidney transplants are tolerogenic in large animal models. CD4+ T regulatory cells specific for HLA-B*1501-derived peptide p37-MA (DSDAASPRMAPRAPWIEQ) developed in a long term (>12 yrs) tolerant patient who received a HLA-B*1501 mismatched, HLA class II closely matched renal allograft. We hypothesized that class II matching favored Treg development by allowing allopeptide presentation on either recipient [DR4/DQ7+] or donor [DR4/DQ8+] APC. Indirect pathway CD4+ T cell clones were generated from recipient PBMC by sorting antigen-stimulated, proliferating cells. Most clones responded to p37-MA-pulsed DQ7+B*1501− autologous, but not to DQ8+B*1501+ donor B-LCL. However, some clones responded to both; in fact, one responded even more strongly to donor B-LCL than to p37-MA-pulsed autologous B-LCL. P37-MA contained a DQ8-binding motif and induced strong TH1 responses from DQ8 but not DQ6 transgenic mice. Microchimerism,, was found to be enriched in the dendritic cells cultured from adherent PBMC. These data support the concept that, when the donor is MHC class II closely matched, a “hybrid” form of allorecognition (direct/indirect) occurs. This may favor the generation of beneficial form of indirect pathway alloreactivity, i.e. allopeptide-specific CD4 T regulatory cells, in the context of long term DC microchimerism.

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Regulatory functions of human CD4+ T cells recognizing allopeptides in the context of self-HLA class II

Cited by 16 publications

References 40 publications

Human CD4+CD25low Adaptive T Regulatory Cells Suppress Delayed-Type Hypersensitivity during Transplant Tolerance

Human CD4+CD25low Adaptive T Regulatory Cells Suppress Delayed-Type Hypersensitivity during Transplant Tolerance

The human alloreactive CD4+ T-cell repertoire is biased to a Th17 response and the frequency is inversely related to the number of HLA class II mismatches

Analysis of indirect pathway CD4+ T cells in a patient with metastable tolerance to a kidney allograft

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