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

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.