Lethal murine graft-versus-host disease induced by donor γ/δ expressing T cells with specificity for host nonclassical major histocompatibility complex class Ib antigens

Bruce R. Blazar, Patricia A. Taylor, Angela Panoskaltsis-Mortari, Terrence A. Barrett, Jeffrey A. Bluestone, Daniel A. Vallera

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Although T-cell receptor (TCR) α/β expressing cells have a well-known role in graft-versus-host disease (GVHD) generation, the role of TCR γ/δ expressing cells in this process has remained unclear. To elucidate the potential function of TCR γ/δ cells in GVHD, we have used transgenic (Tg) H-2(d) mice (termed G8) that express γ/δ heterodimers on a high proportion of peripheral T cells. In vitro, G8 Tg γ/δ T cells proliferate to and kill C57BL/6 (B6) (H-2b) which express gene products (T10b and T22b) from the nonclassical major histocompatibility complex (MHC) class Ib H-2T region. The infusion of G8 Tg (H-2T(d)) TCR γ/δ cells into lethally irradiated [900 cGy total body irradiation (TBI)] B6 (H-2b) mice resulted in the generation of lethal GVHD characterized histologically by destruction of the spleen, liver, lung, and colon. Lethal GVHD was prevented by the injection of anti-TCR γ/δ monoclonal antibodies. Immunohistochemical analysis of B6 recipients post- bone marrow transplantation (BMT) confirmed that G8 Tg TCR γ/δ cells infiltrated GVHD target tissues (skin, liver, colon, and lung) and were absent in recipients treated with anti-TCR γ/δ monoclonal antibodies (MoAbs) but not anti-CD4 plus anti-CD8 MoAbs. In contrast, injection of TCR γ/δ+ cells into irradiated (900 cGy TBI) B6.A-TIaa BoyEg mice that do not express either T10b or T22b did not induce lethal GVHD. Similarly, in a different GVHD system in which sublethal irradiation without bone marrow (BM) rescue was used, B6 but not B6.A-TIaa/BoyEg mice were found to be susceptible to TCR γδ+ cell mediated GVHD-induced lethality characterized by an aplasia syndrome. These results demonstrate that TCR γ/δ cells have the capacity to cause acute lethal GVHD in mice and suggest that nonclassical MHC class Ib gene products expressed on GVHD target organs are responsible for G8 Tg TCR γ/δ+ cell mediated lethality.

Original languageEnglish (US)
Pages (from-to)827-837
Number of pages11
JournalBlood
Volume87
Issue number2
DOIs
StatePublished - Jan 15 1996

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