Vβ spectratype analysis reveals heterogeneity of CD4+ T-cell responses to minor histocompatibility antigens involved in graft-versus-host disease: Correlations with epithelial tissue infiltrate

Abstract

Lethal graft-versus-host disease (GVHD) can be induced after hematopoietic stem cell transplantation between major histocompatibility complex-matched murine strains expressing multiple minor histocompatibility antigen (miHA) differences. In the C57BL/6By (B6) → C.B10-H2b/LiMcdJ (BALB.B) irradiation model, both CD4+ and CD8+ donor T cells can mediate lethal GVHD, whereas in the B6 → CXB-2/By (CXBE) model, in which the recipient expresses a subset of BALB.B miHA, only the CD8+ T cells are lethal. Phenotypic analysis of CD4+ T cells collected from the thoracic duct lymphocyte pool of recipient mice had indicated expansion of the donor T-cell receptor Vβ6-9 families in BALB.B recipients, and only Vβ7 and Vβ9 populations in CXBE mice. CDR3-size spectratyping, used to further analyze these responses, revealed overlapping oligoclonal expansion of Vβ4, Vβ6-10, and Vβ12-14 families in both BALB.B and CXBE recipients injected with host-presensitized B6 T cells. In addition, the B6 → BALB.B CD4+ T-cell response appeared to involve the recognition of unique BALB.B-specific miHA, indicated by additional skewing of Vβ2 and Vβ11 families. On the other hand, the B6 → CXBE strain combination exhibited unique skewing of the Vβ16 and Vβ18 families. Immunohistochemical staining of lingual epithelial sections from BALB.B recipients of naive B6 CD4+ T cells correlated with the involvement of several of the spectratype-skewed Vβ families in GVHD lesions. Furthermore, magnetic cell separation techniques were used to positively select the spectratype-skewed Vβ families from the donor B6 CD4+ T cells; the former were found to have significant GVHD potential upon transplantation into lethally irradiated BALB.B recipients. In contrast, mice that received transplants from the unskewed Vβ families all survived with minimal symptoms of GVHD. Taken together, these results demonstrate that the expansion of particular Vβ families, as identified by spectratype analysis, correlates with the induction and pathogenesis of lethal GVHD.