Role of Immunoregulatory Donor T Cells in Suppression of Graft-Versus-Host Disease Following Donor Leukocyte Infusion Therapy

• Published in: The Journal of immunology (1950) Vol. 163; no. 12; pp. 6479 - 6487
• Main Authors: Johnson, Bryon D, Becker, Emily E, LaBelle, James L, Truitt, Robert L
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.12.1999
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; CD4 Antigens - biosynthesis; CD8 Antigens - biosynthesis; Cell Differentiation - genetics; Cell Differentiation - immunology; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Histocompatibility Testing; Immunophenotyping; Isoantibodies - administration & dosage; Leukocyte Transfusion - adverse effects; Lymphocyte Activation; Lymphocyte Count; Lymphocyte Depletion; Major Histocompatibility Complex - immunology; Mice; Mice, Inbred AKR; Mice, Inbred C57BL; Mice, Knockout; Radiation Chimera - immunology; Receptors, Antigen, T-Cell, alpha-beta - biosynthesis; Spleen - cytology; Spleen - transplantation; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Helper-Inducer - immunology; Thy-1 antigen; Thy-1 Antigens - biosynthesis; Thy-1 Antigens - immunology; Thymus Gland - cytology; Thymus Gland - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.12.6479

In murine models of allogeneic bone marrow transplantation (BMT), MHC-mismatched recipients given a delayed infusion of donor leukocytes (DLI) at 21 days posttransplant develop significant GVHD whereas MHC-matched recipients do not. The current study was initially designed to test the hypothesis that small numbers of T cells in the MHC-mismatched donor bone marrow (BM) graft exacerbated graft-vs-host disease (GVHD) when DLI was administered at 21 days after BMT. Ex vivo depletion of Thy1+ cells from the donor BM had no impact on the severity of GVHD after DLI. However, depletion of donor T cells in vivo with a Thy1 allele-specific mAb given after BMT resulted in significantly more severe GVHD after DLI. Similar results were obtained in a MHC-matched model of allogeneic BMT, indicating that this was a general phenomenon and not model dependent. These results indicated that a population of donor-derived Thy1+ cells suppressed graft-vs-host reactivity after DLI. Results of experiments with thymectomized recipients demonstrated that an intact thymus was required for generation of the immunoregulatory donor cells. Experiments using TCR beta-chain knockout mice as BM donors indicated that the immunosuppressive Thy1+ cells coexpressed alphabetaTCR heterodimers. Similar experiments with CD4 and CD8 knockout donor BM suggested that the immunoregulatory Thy1+alphabetaTCR+ cells consisted of two subpopulations: a CD4+CD8- subpopulation and a CD4-CD8- subpopulation. Together, these results show that thymus-derived, Thy1+alphabetaTCR+ donor cells generated early after allogeneic BMT suppress the graft-vs-host reactivity of T cells given as DLI. These cells may mediate dominant peripheral tolerance after allogeneic BMT.