Distinct expression and inhibitory function of B and T lymphocyte attenuator on human T cells

Section: Discussionmentioning

confidence: 99%

Anti-Programmed Cell Death 1 Antibody Reduces CD4+PD-1+ T Cells and Relieves the Lupus-Like Nephritis of NZB/W F1 Mice

Kasagi

Kawano

Okazaki

et al. 2010

“…With regard to therapeutic aspects, agonistic mAbs that crosslink BTLA and suppress the proliferation and production of cytokines such as IL-2 and IFN-␥ by human (26) and murine (27) T cells are reported, and administration of HVEM-Ig can also dampen immune responses (25, 28 -30). Our data suggest that the enhancement of HVEM expression by gene therapy or other approaches may be an additional tool for immune therapy, as may consideration of the BTLA-HVEM pathway during in vitro efforts to scale-up, for eventual in vivo application, large numbers of Tregs (31,32).…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cell Expression of Herpesvirus Entry Mediator Suppresses the Function of B and T Lymphocyte Attenuator-Positive Effector T Cells

Tao

Wang

Murphy

et al. 2008

The binding of herpesvirus entry mediator (HVEM) to B and T lymphocyte attenuator (BTLA) is known to activate an inhibitory signaling cascade in effector T (Teff) cells, but we now report that the HVEM-BTLA pathway is also important to the suppressive function of regulatory T cells (Tregs). Although naive T cells up-regulated BTLA upon TCR activation, Treg expression of BTLA remained low, regardless of TCR activation. Moreover, BTLA−/− CD4+CD25+ Tregs had normal suppressive activity, whereas BTLA−/− Teff cells were more resistant than wild-type Teff cells to suppression by Tregs, suggesting BTLA expression by Teff cells was required for their suppression by Tregs. In contrast to BTLA, HVEM expression was comparable in naive Tregs vs Teff cells, but after stimulation HVEM expression was quickly down-regulated by Teff cells, whereas HVEM was further up-regulated by Tregs. HVEM−/− Tregs had decreased suppressive activity as compared with wild-type Tregs, indicating that Treg expression of HVEM was required for optimal suppression. Consistent with this, T cells from Scurfy mice (FoxP3 mutant) lacked HVEM gene expression, and adoptively transferred wild-type but not HVEM−/− Tregs were able to control alloresponses in vivo by normal Teff cells. Our data demonstrate that Tregs can exert their effects via up-regulation of the negative costimulatory ligand HVEM, which upon binding to BTLA expressed by Teff cells helps mediate the suppressive functions of Tregs in vitro and in vivo.

“…BTLA is expressed on B cells, T cells, and dendritic cells in all strains of mice whereas its expression on NK cells and macrophages is limited to C57BL/6 mice (8,9), which model human expression well (10). HVEM engagement by BTLA induces tyrosine phosphorylation and the association of BTLA with the SHP-2 tyrosine phosphatase to repress Ag-driven T cell proliferation (7).…”

mentioning

confidence: 99%

Cutting Edge: B and T Lymphocyte Attenuator Signaling on NKT Cells Inhibits Cytokine Release and Tissue Injury in Early Immune Responses

Miller

Sun

2009

The role of coinhibition in an immune response is thought to be critical for the contraction of an adaptive immune response in its waning phases. We present evidence that B and T lymphocyte attenuator (BTLA) coinhibitory signaling is required to temper early inflammation. Using an in vivo Con A challenge model of acute hepatitis, we observed reduced survival and increased early serum cytokine secretion in BTLA−/− mice as compared with wild-type mice. In vitro, liver mononuclear cells from BTLA−/− mice are hyperresponsive to anti-CD3, Con A, and α-galactosylceramide stimulation and secrete higher levels of TNF-α, IFN-γ, IL-2, and IL-4. We found this was in part due to negative regulation of NKT cells by BTLA, as early cytokine inhibition from whole liver mononuclear cells or purified NKT cells depends upon BTLA signaling. Overall, our data demonstrate that coinhibition is active in early immune responses through BTLA regulation of NKT cells.