T lymphocyte indifference to extrathymic islet allografts

Abstract

Although the deletion of self-reactive T cells maturing in the thymus is well documented, the nature of tolerance to Ags expressed exclusively on peripheral (extrathymic) tissues is less clear. Numerous studies have examined T cell reactivity to transgene-encoded Ags expressed in the periphery through tissue-specific promoters. These studies have yielded varied results concerning the degree and nature of tolerance induced to these Ags, ranging from T cell clonal deletion or inactivation to clonal "ignorance" of the peripheral transgene-encoded Ag. Furthermore, the relationship of these findings to the generation and maintenance of transplantation tolerance to extrathymic tissue allografts remains unclear. Whereas transgenic studies represent a developmental form of tolerance, grafted tissues are introduced into adult, nontolerant recipients. To relate these two model systems, we determined whether extrathymic tissue allografts could induce a developmental form of tolerance. As a model of extrathymic alloantigen expression, pancreatic islet allografts, depleted of donor APCs, were established in the periphery of severe combined immune-deficient (SCID) mice. We then examined the potential donor reactivity of adoptively transferred bone marrow-derived T cell precursors maturing in the presence of the established peripheral allograft. Such T cells were neither activated nor tolerized either in vitro or in vivo, suggesting that T cells are indifferent to Ags expressed by extrathymic islet allografts when presented in the absence of a second costimulatory signal.