Evidence for a Thymus‐Dependent Form of Tolerance that is Not Based on Elimination or Anergy of Reactive T cells

Abstract

The avian embryo has provided an appropriate model to study the ontogeny of the primary lymphoid organs, thymus and bursa of Fabricius. By using the quail-chick marker system the embryonic origin of the highly intricate cell components which form these organs could be traced back to the initial endodermal, mesodermal and ectodermal germ layers. The timing and dynamics of the incoming and outcoming flows of hemopoietic cells which characterize their lymphopoietic activity could be revealed in both quail and chick embryos. This knowledge served as a basis for an investigation on the role of the epithelial component of the thymus (derived from the pharyngeal endoderm) on tolerance to tissue graft and, by extension, tolerance to self. When this work was undertaken, the prevailing view was that exposure of the developing immune system to foreign antigens in the embryo allows them to be assimilated to self components in the mature animal. In fact, this was found to be true for allogeneic grafts between MHC-distinct chickens, of certain tissues, such as for instance wing tissues. However, in heterospecific transplantations, i.e. when a limb bud was grafted from quail to chick embryos, the chick host acutely rejected the foreign limb soon after birth. In contrast, grafts of the quail thymic epithelial (TE) rudiment resulted in the development of a chimeric thymus in which the foreign epithelial component was not only tolerated but able to induce full tolerance of the grafted wing from the same donor. By monitoring the amount of quail TE implanted we showed in addition that only part of the peripheral T-cell population had to differentiate in the context of the quail epithelial cells to induce tolerance to quail tissues. This pointed to the generation in the thymus of regulatory T cells, coexisting with specific anti-quail reactive T cells, but able to inhibit them from reacting against the quail wing antigenic determinants. A mammalian model was then devised to further study this mechanism of tolerance that we have qualified as "dominant" by opposition to the current model based on either clonal elimination or anergy which can be considered as recessive or passive. Nude mice of MHC type A were grafted with TE of E10 type B embryos. They became reconstituted for T-cell function but tolerant for B skin allografts. Spleen cells from such tolerant animals injected to naive A nude mice reconstituted T cell function in the recipient and transferred the tolerance to B skin grafts. Reducing the number of donor cells resulted in the segregation of the two phenomena. For low numbers the recipients were restored but not tolerant, thus showing the coexistence in the tolerant donor of anti-B reactive T cells together with regulatory cells able to abolish their reactivity against B determinants. Other experiments demonstrated that TE-induced tolerance does not rely on clonal deletion or anergy. This was shown on systems where elimination of cells directed toward superantigens was screened. It turned out that tolerance to skin grafts a...

Regulatory T cells – a brief history and perspective

“…Yet there are other important studies that have contributed to our current conceptualization of T R cells. For example, dominant transplantation tolerance can be established by administration of anti-CD4 or other mAb, the immunosuppressant cyclosporine A, or transplanting allogeneic or xenogeneic thymic epithelial cells into embryos [72][73][74]. There is recent evidence that these types of graft tolerance are maintained by suppressive CD4 + T cells, which are functionally and phenotypically similar to Foxp3 + natural T R cells [75].…”

Heterogeneity of natural Foxp3 + T cells: A committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity

“…Early studies of autoimmunity provoked by neonatal thymectomy in mice (1), and of transplantation tolerance to tissue grafts induced by previous transplantation of pure thymic epithelium in birds and in mice (9), indicated that natural T reg represent a distinct thymus-committed lineage. Although it has also become evident that further Foxp3 ϩ T reg can be generated from peripheral naïve CD4 ϩ T cells upon ''tolerogenic'' antigen presentation in vivo or activation in the presence of transforming growth factor (TGF)-␤ in vitro (10,11), this notion of a stable lineage has been strengthened by data showing that the phenotypic and functional features of CD4 ϩ CD25 ϩ T reg are stably maintained after many rounds of cell division in vitro and in vivo (1).…”

Natural Immunological Tolerance: On Time and Space Again

“…This is wrong on two accounts. First, other tissue grafts, such as skin, at birth or even in utero [11] fail to induce tolerance to themselves, as first pointed out by Billingham & Silvers [19] but previously reported by Medawar & Woodruff [20], and then extensively confirmed in birds [14]. Second, as later confirmed by other investigators [21], TE does induce tolerance to other tissues, if transplanted into allogeneic, athymic mice.…”

“…The original work of Le Douarin and colleagues in birds, as well as its developments in the mouse, have established that TE establishes tolerance towards a variety of peripheral tissues (all ? ), except haemopoietic cells [11,12] †. This tolerance is robust, and cannot be abrogated by repeated priming with 'professional' antigen-presenting cells, before or after tissue grafts [12].…”