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

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 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.

Microchimerism is strongly correlated with tolerance to noninherited maternal antigens in mice

“…Such T R cells have recently been shown to be the extremely potent in inducing tolerance to allografts in mice, 51 and may help explain the acceptance, after short-term immunosuppression, of renal allografts that are MHC class I-mismatched, but MHC class II-matched. [52][53][54] In conclusion, we have found a striking correlation between MMc and NIMA-specific T R cells capable of suppressing both DTH and lymphoproliferative responses of T E cells in adult mice. The data suggest that maintenance of MMc is critically intertwined with NIMA-induced regulation and T R cell generation, which depends on oral exposure to maternal antigens via nursing, and may explain why some but not all offspring become microchimeric and tolerant to a maternal antigen-expressing allograft.…”

Linked Suppression Across an MHC-Mismatched Barrier in a Miniature Swine Kidney Transplantation Model.

“…Also consistent with our data, they reported that CD4 +CD25+ cells from both tolerant and naïve animals possessed suppressive activity, while CD4 +CD25-cells were only suppressive when isolated from tolerant animals. Evidence for the function of CD4+CD25 low adaptive Tregs has recently been reported in humans (33), suggesting that the mechanism of tolerance in these models may be similar to that observed in humans.…”

Bidirectional alloreactivity

“…appear to be critical, and there is a distinctive pattern of Treg and B cell infiltration in the cortex that occurs within 72 h of graft placement. 38,39 Similar patterns of Treg-enriched organized lymphoid structures (TOLS) have been described in accepted monkey [40][41][42] and human 43 kidney allografts, while elevated naive B cell counts in the periphery and CD20 mRNA in urine samples of tolerant patients have recently been described. 44,45 In addition, tolerance to a kidney transplant also involves anergy.…”