Antigen recognition by MHC-incompatible cells of a human mismatched chimera

Tetanus toxin (TT)-specific T cell clones of donor origin were obtained from a patient with severe combined immunodeficiency (SCID) successfully reconstituted by transplantation of allogeneic fetal liver and thymus cells from two different donors performed 10 yr ago. A series of these clones recognized TT in the context of "allo" class II HLA determinants expressed by recipient APC. The restriction element of two T cell clones with the HLA phenotype of the first donor (HLA-DR1,8) and one T cell clone with the HLA phenotype of the second transplant (HLA-DR3,9) was HLA-DR4 of the recipient, whereas other T cell clones derived from the second transplant recognized TT in the context of HLA- DR5 of the recipient's APC. These latter T cell clones were not able to proliferate in response to TT when autologous APC were used. These data demonstrate that recipient and donor cells having different HLA phenotypes could cooperate across the allogeneic barrier and that MHC restriction of antigen (Ag) recognition is independent from the MHC genotype of the T cells but is influenced by the environment in which the T cells mature. We also isolated T cell clones that were able to recognize processed TT presented by all allogeneic EBV cell lines tested, indicating that the Ag specificity of these clones was not restricted by a particular class II MHC molecule. The Ag-specific proliferative response of one of these clones could be blocked by anti- class II MHC mAbs. These results demonstrate that in addition to Ag recognition in the context of specific class II MHC Ags, other types of Ag-specific responses may occur in this human chimera. It is not clear whether this "allo" plus Ag recognition is the result of education of transplanted fetal cells in the host thymus. Taking into consideration our previous findings indicating that alloreactive T cell clones specific for the recipient cells could be isolated in vitro from the PBL of the same patient, our data suggest that the mechanism for deletion of self-reactive clones and the generation of MHC-restricted responses are different.

[1]  R. Palmiter,et al.  The effect of thymus environment on T cell development and tolerance , 1988, Cell.

[2]  J. D. de Vries,et al.  Autoreactive T cell clones specific for class I and class II HLA antigens isolated from a human chimera , 1988, The Journal of experimental medicine.

[3]  J. Sprent,et al.  T Cell Selection in the Thymus , 1988, Immunological reviews.

[4]  J. Banchereau,et al.  The low-affinity receptor for IgE (CD23) on B lymphocytes is spatially associated with HLA-DR antigens , 1988, The Journal of experimental medicine.

[5]  R. Sorensen,et al.  Long-term immunological reconstitution by peripheral blood leucocytes in severe combined immune deficiency disease: implications for the role of mature lymphocytes in histocompatible bone marrow transplantation. , 1986, Clinical and experimental immunology.

[6]  J. Banchereau,et al.  Cooperation between major histocompatibility complex mismatched mononuclear cells from a human chimera in the production of antigen-specific antibody. , 1986, The Journal of clinical investigation.

[7]  D. Longo,et al.  Bone marrow-derived thymic antigen-presenting cells determine self-recognition of Ia-restricted T lymphocytes. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[8]  W. V. van Blitterswijk,et al.  Serum-free medium for generation and propagation of functional human cytotoxic and helper T cell clones. , 1984, Journal of immunological methods.

[9]  D. Mann,et al.  Transformation of human umbilical cord blood T cells by human T-cell leukemia/lymphoma virus. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Touraine.  Bone‐Marrow and Fetal‐Liver Transplantation in Immunodeficiencies and Inborn Errors of Metabolism: Lack of Significant Restriction of T‐Cell Function in Long‐Term Chimeras Despite HLA‐Mismatch , 1983, Immunological reviews.

[11]  R. Good,et al.  In vitro differentiation of human marrow T cell precursors by thymic factors in severe combined immunodeficiency. , 1981, Transplantation.

[12]  A. Singer,et al.  Self recognition in allogeneic radiation bone marrow chimeras. A radiation- resistant host element dictates the self specificity and immune response gene phenotype of T-helper cells , 1981, The Journal of experimental medicine.

[13]  V. Quaranta,et al.  Purification of immunologically functional subsets of human Ia-like antigens on a monoclonal antibody (Q5/13) immunoadsorbent. , 1980, Journal of immunology.

[14]  R. Zinkernagel,et al.  Restriction specificities, alloreactivity, and allotolerance expressed by T cells from nude mice reconstituted with H-2-compatible or - incompatible thymus grafts , 1980, The Journal of experimental medicine.

[15]  P. Fink,et al.  The Influence of Thymus H‐2 Antigens on the Specificity of Maturing Killer and Helper Cells , 1978, Immunological reviews.

[16]  R. Zinkernagel,et al.  On the thymus in the differentiation of "H-2 self-recognition" by T cells: evidence for dual recognition? , 1978, The Journal of experimental medicine.

[17]  R. Good,et al.  Thymic activity in severe combined immunodeficiency diseases. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Zinkernagel,et al.  Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytes choriomeningitis , 1974, Nature.

[19]  M. Roncarolo,et al.  Fetal tissue transplantation, bone marrow transplantation and prospective gene therapy in severe immunodeficiencies and enzyme deficiencies. , 1987, Thymus.

[20]  R. Hodes.  MHC Restricted Recognition by Cloned T Cells , 1986 .

[21]  C. Griscelli,et al.  Self Education after Mismatched HLA Haploidentical Bone Marrow Transplantation , 1985 .

[22]  B. Dupont,et al.  Transplantation of hematopoietic cells for lethal congenital immunodeficiencies. , 1983, Birth defects original article series.

[23]  L. Gebuhrer,et al.  A possible new HLA-DR allele. , 1983, Human immunology.

[24]  J. Borst,et al.  Characterization of monoclonal antibodies against cell surface molecules associated with cytotoxic activity of natural and activated killer cells and cloned CTL lines. , 1983, Hybridoma.

[25]  J. Klein,et al.  Mhc restriction and Ir genes. , 1982, Advances in cancer research.

[26]  E. Gelfand,et al.  Transplantation in severe combined immunodeficiency disease with hl-a identical bone marrow. , 1975, Birth defects original article series.