Cd4+/Cd25+ Cells Regulate Cd8 Cell Anergy in Tolerant Mice

493

384

An elusive goal in transplanting organs across histocompatibility barriers has been the induction of specific tolerance to avoid graft rejection. A considerable body of evidence exists that the thymus produces regulatory T cells that suppress the response of other T cells to antigenic stimulation. We report that TGF-β can induce certain CD4+ T cells in the naive (CD45RA+RO−) fraction in human peripheral blood to develop powerful, contact-dependent suppressive activity that is not antagonized by anti-TGF-β or anti-IL-10 mAbs. The costimulatory effects of TGF-β on naive CD4+ T cells up-regulated CD25 and CTLA-4 expression, increased their transition to the activated phenotype, but decreased activation-induced apoptosis. Suppressive activity was concentrated in the CD25+ fraction. These CD4+CD25+ regulatory cells prevented CD8+ T cells from proliferating in response to alloantigens and from becoming cytotoxic effector cells. Moreover, these regulatory cells exerted their suppressive activities in remarkably low numbers and maintained these effects even after they are expanded. Once activated, their suppressive properties were Ag nonspecific. Although <1% of naive CD4+ T cells expressed CD25, depletion of this subset before priming with TGF-β markedly decreased the generation of suppressive activity. This finding suggests that CD4+CD25+ regulatory T cells induced ex vivo are the progeny of thymus-derived regulatory T cells bearing a similar phenotype. The adoptive transfer of these regulatory T cells generated and expanded ex vivo has the potential to prevent rejection of allogeneic organ grafts.

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 96%

See 1 more Smart Citation

A Role for TGF-β in the Generation and Expansion of CD4+CD25+ Regulatory T Cells from Human Peripheral Blood

Yamagiwa

Gray

Hirano

et al. 2001

493

384

“…Our observation that CD8 ϩ T cells from neonatally tolerant mice are able to suppress the response to donor alloantigens is consistent with a previous report demonstrating that anti-donor CD8 ϩ T cells persist after neonatal induction of transplantation tolerance but are suppressed by CD4 ϩ T cells with regulatory properties (33). Because we found that anti-donor CD4 ϩ Th2 activities are themselves inhibited by CD8 ϩ T cells, one can conclude that CD4 ϩ and CD8 ϩ T cell responses against donor alloantigens are indeed cross-regulated in allotolerant mice.…”

Section: Discussionsupporting

confidence: 93%

CD8+ T Lymphocytes Regulating Th2 Pathology Escape Neonatal Tolerization

Adams

Nagy

Paulart

et al. 2003

Transplantation tolerance induced by neonatal injection of semiallogeneic spleen cells is associated in several strain combinations with a pathological syndrome caused by Th2 differentiation of donor-specific CD4+ T lymphocytes. We investigated the role of host CD8+ T cells in the regulation of this Th2 pathology. IgE serum levels and eosinophilia significantly increased in BALB/c mice neonatally injected with (A/J × BALB/c)F1 spleen cells when CD8+ T cells were depleted by administration of anti-CD8 mAb or when β2-microglobulin-deficient mice were used as recipients. In parallel, increased serum levels of IL-5 and IL-13 were measured in blood of tolerant CD8+ T cell-deficient mice. Whereas neonatally injected mice were unable to generate anti-donor cytotoxic effectors, their CD8+ T cells were as efficient as control CD8+ T cells in reducing the severity of Th2 pathology and in restoring donor-specific cytotoxicity in vitro after in vivo transfer in β2-microglobulin-deficient mice. Likewise, CD8+ T cells from control and tolerant mice equally down-regulated the production of Th2 cytokines by donor-specific CD4+ T cells in vitro. The regulatory activity of CD8+ T cells depended on their secretion of IFN-γ for the control of IL-5 production but not for IL-4 or IL-13. Finally, we found that CD8+ T cells from 3-day-old mice were already able to down-regulate IL-4, IL-5, and IL-13 production by CD4+ T cells. We conclude that regulatory CD8+ T cells controlling Th2 responses are functional in early life and escape neonatal tolerization.

“…Although the exact mechanism for the apparent selective maintenance of the Th2 cells is unknown, it has been suggested that the primary Th1 cells that arise upon neonatal exposure to Ag are more vulnerable to apoptosis (8). Also, recent investigations have envisioned the involvement of regulatory (9) and CD4 ϩ Thy1 Ϫ (10) T cells to maintain such biased neonatal immunity. Furthermore, although neonatal tolerance has proved effective in conferring resistance against autoimmunity (11)(12)(13)(14), the mechanism initiating and perpetuating the biased neonatal immunity is still undefined.…”

mentioning

confidence: 99%

Neonatal Immunity Develops in a Transgenic TCR Transfer Model and Reveals a Requirement for Elevated Cell Input to Achieve Organ-Specific Responses

Legge

Min

et al. 2001

In recent years, it has become clear that neonatal exposure to Ag induces rather than ablates T cell immunity. Moreover, rechallenge with the Ag at adult age can trigger secondary responses that are distinct in the lymph node vs the spleen. The question addressed in this report is whether organ-specific secondary responses occur as a result of the diversity of the T cell repertoire or could they arise with homogeneous TCR-transgenic T cells. To test this premise, we used the OVA-specific DO11.10 TCR-transgenic T cells and established a neonatal T cell transfer system suitable for these investigations. In this system, neonatal T cells transferred from 1-day-old DO11.10/SCID mice into newborn (1-day-old) BALB/c mice migrate to the host’s spleen and maintain stable frequency. The newborn BALB/c hosts were then given Ig-OVA, an Ig molecule carrying the OVA peptide, and challenged with the OVA peptide in CFA at the age of 7 wk; then their secondary responses were analyzed. The findings show that the lymph node T cells were deviated and produced IL-4 instead of IFN-γ and the splenic T cells, although unable to proliferate or produce IFN-γ, secreted a significant level of IL-2. Supply of exogenous IL-12 during Ag stimulation restores both proliferation and IFN-γ production by the splenic T cells. This restorable form of splenic unresponsiveness referred to as IFN-γ-dependent anergy required a transfer of a high number of neonatal DO11.10/SCID T cells to develop. Thus, the frequency of neonatal T cell precursors rather than repertoire diversity exerts control on the development of organ-specific neonatal immunity.