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* Department of Pathology and Center for Immunology and
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110
B and T lymphocyte attenuator (BTLA; CD272) can deliver inhibitory signals to B and T cells upon binding its ligand herpesvirus entry mediator. Because CD28, CTLA-4, programmed death-1, and ICOS regulate the development of acute graft-vs-host disease (GVHD), we wished to assess if BTLA also played a role in this T cell-mediated response. In the nonirradiated parental-into-F1 model of acute GVHD, BTLA+/+ and BTLA–/– donor lymphocytes showed equivalent engraftment and expansion during the first week of the alloresponse. Unexpectedly, BTLA–/– donor T cells failed to sustain GVHD, showing a decline in surviving donor cell numbers beginning at day 9 and greatly reduced by day 11. Similarly, inhibition of BTLA-herpesvirus entry mediator engagement by in vivo administration of a blocking anti-BTLA Ab also caused reduced survival of donor cells. Microarray analysis revealed several genes that were differentially expressed by BTLA–/– and BTLA+/+ donor CD4+ T cells preceding the decline in BTLA–/– donor T cells. Several genes influencing Th cell polarization were differentially expressed by BTLA+/+ and BTLA–/– donor cells. Additionally, the re-expression of the IL-7R
subunit that occurs in BTLA+/+ donor cells after 1 wk of in vivo allostimulation was not observed in BTLA–/– donor CD4+ cells. The striking loss of BTLA–/– T cells in this model indicates a role for BTLA activity in sustaining CD4+ T cell survival under the conditions of chronic stimulation in the nonirradiated parental-into-F1 GVHD.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Kenneth M. Murphy, Department of Pathology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: murphy{at}pathology.wustl.edu
2 Abbreviations used in this paper: BTLA, B and T lymphocyte attenuator; 7-AAD, 7-aminoactinomycin; GVHD, graft-vs-host disease; aGVHD, acute GVHD; cGVHD, chronic form of GVHD; HVEM, herpesvirus entry mediator; LIGHT, homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes; LT, lymphotoxin; PD-1, programmed death-1.
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