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-7Ralpha 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.
Hurchla
Michelle A
MA
Department of Pathology and Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
Sedy
John R
JR
Murphy
Kenneth M
KM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology; D002908:Chronic Disease; D004195:Disease Models, Animal; D006085:Graft Survival / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*
D000911:Antibodies, Monoclonal; C488868:BTLA protein, mouse; D007519:Isoantigens; D011971:Receptors, Immunologic