Unexpected Role of B and T Lymphocyte Attenuator in Sustaining Cell Survival during Chronic Allostimulation

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.

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

“…In agreement with the concept that BTLA functions as a prosurvival molecule for T cells is the fact that the engagement of BTLA on donor alloreactive T cells is required for their survival in a graft versus host disease murine model. 46,51 Thus, a single injection of an agonistic anti-BTLA antibody (clone 6A6) at the time of allogeneic bone marrow transplantation was sufficient to prevent GvHD through a mechanism that was mediated by donor Tregs. 51,52 The agonistic effect of the anti-BTLA antibody treatment and not the blockade of the interaction of HVEM/ BTLA on donor CD4 effector cells promoted a rapid contraction of the CD4 T-cell-mediated allogeneic immune response due to impaired survival of donor T cells expanding in response to lymphopenia in conditioned hosts and to an advantageous and competitive homeostatic expansion of Tregs that were responsible for prevention of the disease.…”

“…This observation of impaired donor alloreactive BTLAdeficient T-cell survival during the course of Graft versus Host Disease (GvHD), which promotes the pathology resolution, indicates that BTLA may also play a role in alloreactive T-cell survival. 46 The BTLA/HVEM interaction is also essential for the homeostatic control of CD8a 2 dendritic cell numbers. Indeed, HVEM-and BTLA-deficient mice displayed an increased number of CD8a 2 dendritic cells.…”

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

“…A prosurvival role of BTLA was initially observed in a chronic GvHD model in which adoptively transferred BTLA ¡/¡ splenocytes initially expanded in recipient mice but could not persist long term, suggesting that the memory T-cell function was compromised. 36 Recently, another study showed a prosurvival role of BTLA in vivo in a mouse model of vaccinia virus. 43 In this model, however, BTLA mediated survival and memory development through its expression on dendritic cells.…”

“…5 In the platelet-derived growth factor (PDGF) receptor, this YXN motif has been found to bind to the signaling adaptor protein Grb-2 following phosphorylation of the tyrosine, leading to recruitment of phosphatidylinositol 3' kinase (PI-3K) and activation of Akt through serine phophorylation. 8,9,36 This suggests that HVEM-BTLA signaling could in fact have a prosurvival effect on TIL. To directly test whether BTLA ligation results in initiation of a prosurvival signal via phosphorylated Akt (pAkt), TIL were sorted into CD8 C BTLA C and CD8 C BTLA ¡ subsets and stimulated in vitro with HVEM-Fc fusion protein and anti-CD3 antibody.…”

The TNF receptor and Ig superfamily members form an integrated signaling circuit controlling dendritic cell homeostasis

“…For example, HVEM-BTLA pathway regulates acceptance of partially MHC-mismatched cardiac allograft [58]. BTLA expression was also found to be highly induced on anergic CD4+ T cells [59]. The treatment of mice infected with Plasmodium berghei ANKA with an agonist anti-BTLA mAb prevented the genesis of experimental cerebral malaria by restricting the number of T lymphocytes sequestered in the brain during infection [60].…”