Putting the brakes on BTLA in T cell–mediated cancer immunotherapy
Chrystal M. Paulos, Carl H. June
Chrystal M. Paulos, Carl H. June
Published December 28, 2009
Citation Information: J Clin Invest. 2010;120(1):76-80. https://doi.org/10.1172/JCI41811.
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Commentary

Putting the brakes on BTLA in T cell–mediated cancer immunotherapy

Abstract

Attenuating coinhibitory molecules for the treatment of cancer is gaining a great deal of attention as a strategy for immunotherapy. The B and T lymphocyte attenuator (BTLA, CD272) is a novel coinhibitory molecule structurally and functionally related to CTLA-4 and PD-1. A study in this issue of the JCI by Derré et al. reveals that BTLA is expressed on virus-specific human CD8+ T cells but is progressively downregulated after their differentiation from a naive to effector phenotype (see the related article beginning on page 157). Surprisingly, tumor-specific human CD8+ T cells continue to express BTLA even after their differentiation to an effector phenotype. Remarkably, vaccination of melanoma patients with CpG led to BTLA downregulation on tumor-specific human CD8+ T cells, concomitant with restoration of their functionality. We discuss these findings in the context of the expanding field of cosignaling molecules and their implications for T cell–based therapies for cancer.

Authors

Chrystal M. Paulos, Carl H. June

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Figure 1

The B7/CD28 family interactions and their function outcomes.

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The B7/CD28 family interactions and their function outcomes. The B7/CD28...
The B7/CD28 family members are characterized by their common immunologlobulin extracellular binding domains, and their signaling pathways are driven mainly by their intracellular, tyrosine-containing motifs. In addition to the specific antigen–dependent signal provided by the MHC-antigen complex to the TCR, the cell-surface interactions involving the B7/CD28 family of cosignaling molecules provide a second signal to T cells to enhance or inhibit the TCR signal, which influences the proliferative capacity and functional fate of the T cell. In addition to CD28 ligation by B7-1 and B7-2, T cell costimulation can be mediated by ligation of inducible costimulator (ICOS) via its ligand ICOS-L or can be mediated by ligation of the newly reported trim-like transcript 2 (TLT-2) via its ligand B7-H3. Also, in addition to CTLA-4, BTLA, CD160, and PD-1, which exert their effects via ligation by their respective ligands, is a new molecule referred to as butyrophilin/B7-like molecule (BTNL2), a coinhibitory molecule that mediates signaling of activator protein 1 (AP1) and nuclear factor of activated T cells (NFAT) via a ligand that remains elusive (as indicated by a question mark). Costimulatory interactions are shown in green, coinhibitory interactions in red. TREMR, triggering receptors expressed on myeloid cells receptor. Adapted with permission from Cell (21).