Figure 2. BTLA expression inhibits tumor-specific human CD8⁺ T cell function, which can be overcome by vaccination with CpG.

In this issue of the JCI, Derré et al. report that naive human CD8⁺ T cells express high levels of the coinhibitory molecule BTLA on their surface. They find that BTLA can inhibit the function of tumor-specific human CD8⁺ T cells. In vivo, vaccination of melanoma patients with CpG dampened this inhibition, at least in part, by downregulating BTLA. (A) The surface expression of BTLA is gradually downregulated during differentiation of virus-specific human CD8⁺ T cells from a naive (CCR7⁺CD45RA⁺) to an effector cell phenotype (CCR7^dimCD45RA^–). These differentiated cells produce high amounts of IFN-γ. (B) The surface expression of BTLA is maintained on tumor Melan-A^Mart-1–specific human CD8⁺ T cells from patients vaccinated with conventional peptide vaccination consisting of a Melan-A_26-35 peptide and incomplete Freund’s adjuvant (IFA) even after their differentiation to an effector phenotype, and this is associated with impaired functionality, as indicated by their reduced capacity to produce IFN-γ. (C) The vaccination of melanoma patients with the TLR agonist CpG led to progressive BTLA downregulation on tumor Melan-A^Mart-1–specific human CD8⁺ T cells and resistance to BTLA-HVEM–mediated functional inhibition and robust production of IFN-γ. These data not only underscore the therapeutic potential of CpG but also reveal the clinical importance of the BTLA pathway.