Oligoclonal expansion of CTLs directed against a restricted number of dominant minor histocompatibility antigens in hemopoietic chimeras.

Abstract

To understand how T cells respond to allogeneic minor histocompatibility Ags (MiHAs), we studied the fate of Thy-1.1+ lymphocytes, as well as their TCR usage and functional activity, in irradiated LP (Thy-1.2+) recipients transplanted with a mixture of C57BL/6 (Thy-1.2+) hemopoietic progenitors supplemented with either low or high numbers of B6.PL lymphocytes (Thy-1.1+). Mice transplanted with low numbers of T cells experienced a dramatic expansion (> or = 10(5)-fold) of donor Thy-1.1+/CD8+ cells during the first 15 days post-transplant. Flow-cytometric analysis and sequencing of junctional nucleotide sequences showed that the nature of this expansion was oligoclonal and involved primarily one or a few clones using V beta 5.1 or V beta 8.1 TCR elements. Expanded T lymphocyte populations displayed MHC-restricted cytotoxicity for a restricted number of MiHAs, that were found in only two peaks following fractionation of LP MiHAs by reverse-phase HPLC. Expansion of donor T cells was limited to the spleen, and short-lived in these recipients that became healthy long-term chimeras without any signs of graft-vs-host disease (GVHD). In contrast, mice transplanted with high numbers of T cells (GVHD+) showed proliferation of Thy-1.1+ donor cells not only in the spleen, but also in the thymus, and recipients died rapidly of GVHD. These results show that: 1) in the MiHA-incompatible transplantation setting, lack of GVHD cannot be explained simply by the absence of antihost T cell responses, 2) GVHD+ recipients present a massive thymic infiltration by donor mature T lymphocytes, and 3) antihost T cell responses are oligoclonal in nature and targeted to only a few MiHAs. These findings shed new light on the pathogenetic mechanisms involved in GVHD and on the selection of the T cell repertoire involved in response to immunodominant MiHAs.