Unexpected role of B and T lymphocyte attenuator in sustaining cell survival during chronic allostimulation

Michelle A. Hurchla, John R. Sedy, Kenneth M. Murphy

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

Abstract

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-7Rα 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.

Original languageEnglish
Pages (from-to)6073-6082
Number of pages10
JournalJournal of Immunology
Volume178
Issue number10
DOIs
StatePublished - May 15 2007

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