BTLA Functions As a T Cell Co-inhibitory Receptor

Binding of HVEM to BTLA or CD160 Inhibits T Cell Activation

B and T lymphocyte attenuator (BTLA) is a co-inhibitory receptor belonging to the CD28 family that is structurally similar to CTLA-4 and PD-1.¹ The extracellular domain of BTLA contains a single IgI-like domain followed by a transmembrane segment and a cytoplasmic tail that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM), which are involved in mediating inhibitory signaling.^2-4 BTLA is expressed on B cells, T cells, natural killer (NK) cells, dendritic cells (DCs), and macrophages.⁵ While naïve CD4⁺ and CD8⁺ T cells express low levels of BTLA, BTLA expression is rapidly up-regulated following T cell activation.^{6, 7} In contrast to the other CD28 family receptors which interact with B7 family ligands, BTLA binds to herpesvirus entry mediator (HVEM), a member of the TNF receptor superfamily.⁸ HVEM is widely expressed on a variety of immune cell types, including dendritic cells, naive T and B cells, NK cells, monocytes, and neutrophils.⁶ Binding of HVEM to BTLA inhibits T cell and B cell activation, proliferation, and cytokine production, and serves as an inhibitory checkpoint regulating the accumulation of dendritic cells in lymphoid tissues.^8-12 Additionally, in contrast to naïve effector T cells which down regulate HVEM expression upon activation, HVEM expression on regulatory T cells is up-regulated upon stimulation and its binding to BTLA, expressed on effector T cells, enhances their suppressive activity.⁷ 

Besides BTLA, HVEM also interacts with the immunoglobulin superfamily (IgSF) receptor, CD160, and the TNF superfamily proteins, Lymphotoxin alpha and      LIGHT.^13-15 While binding of HVEM to BTLA or CD160 delivers an inhibitory signal, HVEM also has the ability to stimulate the effector functions of immune cells on which it is expressed by binding to LIGHT or Lymphotoxin alpha.^{6, 13-15} As a result, HVEM has been described as a molecular switch regulating both co-stimulatory and co-inhibitory signaling.

In cancer, BTLA was reported to be expressed on CD8⁺ T cells isolated from the peripheral blood of melanoma patients and crosslinking of BTLA on these cells with HVEM on melanoma cells was shown to inhibit T cell expansion and IFN-gamma production.¹⁶ A second study demonstrated that BTLA up-regulation on tumor antigen-specific CD8⁺ T cells contributed to their dysfunction, and blockade of BTLA could at least partially restore CD8⁺ T cell proliferation and cytokine production.¹⁷ Additionally, this study demonstrated that blockade of both BTLA and PD-1 could synergistically improve the expansion and proliferation of tumor antigen-specific CD8⁺ T cells, when compared with anti-BTLA or anti-PD-1 treatment alone. The improvement in CD8⁺ T cell proliferation was even further enhanced with blockade of BTLA, PD-1, and TIM-3, suggesting that BTLA, PD-1, and TIM-3 all contribute to the dysfunction of tumor antigen-specific CD8⁺ T cells in melanoma. Based on these observations, BTLA is being investigated by immuno-oncology researchers and clinicians as a potential next generation target for cancer immunotherapy.

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