title: Allorecognition and T cell repertoire selection in severe combined immunodeficiency lacking HLA class II antigens.
abstract: In order to elucidate the role of HLA class II molecules in generation of self-nonself discrimination of human T cells, we have analyzed T cell functions in an HLA class II-negative severe combined immunodeficiency patient. Patient PBL expressed no HLA-DR, -DQ, and -DP antigens as judged by immunofluorescence using mAb, and failed to elicit MLR responses from unrelated controls. Patient PBL contained mature T cells (CD3+ TCR alpha beta+) of the CD4 and CD8 subset, showing an apparently normal TCR diversity, as judged by use of anti-V beta 5, -V beta 6, -V beta 8, -V beta 12, and -V alpha 2 mAb. Patient PBL proliferated in response to anti-TCR/CD3 mAb and PHA, but not against recall Ag, despite immunization, and mounted proliferative, but not cytotoxic, responses against allogeneic cells. To find out whether the MLR responses were a consequence of self-nonself discrimination, the patient HLA-DR and -DQ genotype was determined using sequence specific oligonucleotide probes, revealing DRB1*0401 DQB1*0301 alleles, and MLR were set up against a panel of HLA-DR4 DQw3 stimulators matched or mismatched for DRB1*0401 DQB1*0301. Results showed no MLR against DRB1*0401 DQB1*0301 stimulators, but significant responses against stimulators expressing DRB1*0408 and/or DQB1*0302 alleles. Moreover, the DRB1*0401 DQB1*0301 APC reconstituted proliferation of patient PBL against PPD; this response was completely blocked by an anti-IL-2R (p55) mAb and partially also by anti-HLA-DR and -DQ mAb, indicating recognition of these molecules as restriction element presenting Ag--i.e., as self--by patient T cells. In conclusion, the novel demonstration of self-nonself discrimination by T cells from an HLA class II-negative SCID patient suggests that it may not be absolutely dependent on regular HLA class II expression within the differentiation environment in humans.
authors.affiliation: Department of Pediatrics II, University of Ulm, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Knobloch
authors.forename: M
authors.initials: M
authors.lastname: Ballas
authors.forename: A
authors.initials: A
authors.lastname: Wölpl
authors.forename: W
authors.initials: W
authors.lastname: Friedrich
mesh_terms: D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001483:Base Sequence; D017252:CD3 Complex; D015704:CD4 Antigens / Q000032:analysis; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000032:analysis*; D006801:Humans; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000032:analysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000648:ultrastructure
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D015345:Oligonucleotide Probes; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta