Oligoclonal expansion of CTLs directed against a restricted number of dominant minor histocompatibility antigens in hemopoietic chimeras.
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.
Brochu
S
S
Maisonneuve-Rosemont Hospital Research Center, Montréal, Québec, Canada.
Baron
C
C
Hétu
F
F
Roy
D C
DC
Perreault
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016026:Bone Marrow Transplantation / Q000276:immunology; D002454:Cell Differentiation; D002999:Clone Cells; D017931:DNA Primers; D006086:Graft vs Host Disease / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D007108:Immune Tolerance / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D008969:Molecular Sequence Data; D011828:Radiation Chimera / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018800:Thy-1 Antigens / Q000032:analysis; D013950:Thymus Gland / Q000276:immunology
D017931:DNA Primers; D015778:Minor Histocompatibility Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018800:Thy-1 Antigens