B and T Lymphocyte Attenuator Exhibits Structural and Expression Polymorphisms and Is Highly Induced in Anergic CD4+ T Cells

Abstract

B and T lymphocyte attenuator (BTLA) was initially identified as expressed on Th1 cells and B cells, but recently reported to be expressed by macrophages, dendritic cells, and NK cells as well. To address this discrepancy we generated a panel of BTLA-specific mAbs and characterized BTLA expression under various activation conditions. We report the existence of three distinct BTLA alleles among 23 murine strains, differing both in Ig domain structure and cellular distribution of expression on lymphoid subsets. The BALB/c and MRL/lpr alleles differ at one amino acid residue, but C57BL/6 has nine additional differences and alters the predicted cysteine bonding pattern. The BALB/c BTLA allele is also expressed by B cells, T cells, and dendritic cells, but not macrophages or NK cells. However, C57BL/6 BTLA is expressed on CD11b+ macrophages and NK cells. Finally, in CD4+ T cells, BTLA is expressed most highly following Ag-specific induction of anergy in vivo, and unlike programmed death-1 and CTLA-4, not expressed by CD25+ regulatory T cells. These results clarify discrepancies regarding BTLA expression, suggest that structural and expression polymorphisms be considered when analyzing BTLA in various murine backgrounds, and indicate a possible role in anergic CD4+ T cells.

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

“…Finally, despite the large numbers of hybridoma clones that secrete antibodies against mouse BTLA that are available in the market, they all detect BTLA expression on B cells well; however, their BTLA staining on T cells is negative or weak. 36 This accounts for the impossibility to follow BTLA expression after treatment with an anti-BTLA mAb.…”

“…As the expression of BTLA differs in distinct mouse strains, 21,36 we decided to evaluate the antidonor humoral immune response and the fate of fully MHC-mismatched allogeneic skin grafts in an alternative mouse strain combination (donor B6 to BALB/c recipient mice) that was treated with antibodies that interfered with the BTLA/HVEM pathway. The host antidonor humoral immune response in the BALB/ c recipients was delayed compared with the B6 recipients at day 10 after skin grafting, but they reached similar levels at day 20.…”

B and T Lymphocyte Attenuator Regulates B Cell Receptor Signaling by Targeting Syk and BLNK

“…BTLA is expressed on a wide variety of murine immune cells with varying degrees of surface expression on B, T (CD4 ϩ , CD8 ϩ , and regulatory T), macrophages, dendritic cells, and NK cells (9,13,16). To aid in our understanding of BTLA function in human cell lineages, we analyzed BTLA expression on human primary B cell subsets using a previously described BTLA-specific mAb (4).…”

“…It is most highly expressed on B cells, followed by CD4 ϩ T cells, and lower expression on CD8 ϩ T cells, macrophages, dendritic cells, and NK cells (9,13). During murine B cell development, BTLA expression first appears in pre-B cells and shows increased expression through B cell maturation, with the highest expression on mature B cells (9).…”

The LIGHT and DARC sides of herpesvirus entry mediator

“…BTLA contains immune receptor tyrosine inhibition motifs and upon aggregation recruits tyrosine phosphatases SHP-1 and -2, leading to attenuation of T cell activation (8). BTLA is expressed on activated and anergic T cells, resting B cells, and, at lower levels, on dendritic cells and macrophages (8,9). Surprisingly, HVEM was discovered to be a ligand for BTLA (10,11), providing the first example of a functional interaction between a TNFR and an Ig superfamily member.…”