Evolution of responding CD4+ and CD8+ T-cell repertoires during the development of graft-versus-host disease directed to minor histocompatibility antigens.
Graft-versus-host disease (GVHD) can be induced in lethally irradiated mice after allogeneic bone marrow transplantation between major histocompatibility complex-matched strains expressing multiple minor histocompatibility antigen differences. In the B6 --> BALB.B irradiation model, both CD4(+) and CD8(+) donor T cells have the capacity to mediate lethal GVHD. Previously, CDR3-size spectratyping was used to analyze these T-cell responses at a single early time point (day 5) after transplantation and revealed clonal or oligoclonal expansions of the V beta 2, 4, and 6 to 14 families for the CD4(+) response and of the V beta 4, 6, 8 to 11, and 14 families for the B6 CD8(+) response. Appropriate positive selection of these T-cell receptor V beta-skewed CD4(+) and CD8(+) T-cell subsets and their subsequent transfer into lethally irradiated BALB.B recipients resulted in fatal GVHD induction. In contrast, BALB.B mice transplanted with nonskewed V beta CD4(+) T cells survived, with minimal symptoms of GVHD. This study was undertaken to investigate the evolution of the donor/antihost minor histocompatibility antigen T-cell repertoire responses throughout the course of GVHD development. The results indicated that a number of V beta families were consistently involved throughout the course of GVHD, whereas some V beta families exhibited skewed expansions only in either the early or late stages of disease. In addition, sequence analysis of relevant representative skewed CDR3 bands from the CD4(+) V beta 11(+) and the CD8(+) V beta 14(+) families, both of which exhibited strong consistent responses, demonstrated increased use of the J beta 2.5 and J beta 2.4 segments, respectively, thus identifying the T-cell receptor specificities involved.
Friedman
Thea M
TM
Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Jones
Stephen C
SC
Statton
Debbie
D
Murphy
George F
GF
Korngold
Robert
R
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D016172:DNA Fingerprinting; D019674:Genes, T-Cell Receptor beta / Q000235:genetics / Q000276:immunology*; D006086:Graft vs Host Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology*; D016133:Polymerase Chain Reaction; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D019172:Transplantation Conditioning
D015778:Minor Histocompatibility Antigens; D017260:Receptor-CD3 Complex, Antigen, T-Cell