Chronic lymphocytic leukaemia (CLL) is associated with several humoural and cellular immune abnormalities (Scrivener et al, 2003; Stevenson & Caligaris-Cappio, 2004) that could lead to an inadequate anti-tumour response. The immune surveillance of tumour cells depends on the recognition of antigens presented in the context of human leukocyte receptor HLA class I molecules by cytotoxic T lymphocytes (CTLs), via their T-cell receptors (TCRs) (Rosenberg, 2001). However, antigen alone is insufficient to drive the activation of naive T-cells (Lafferty et al, 1978), and the two-signal model of T-cell activation was proposed. According to this model, the effective activation of naive T cells requires second, antigen independent, co-stimulatory signal provided by the interaction between a costimulatory receptor and its ligand on an antigen-presenting cell (Jenkins et al, 1990; Schwartz et al, 1989). The lack of co-stimulation results in T-cell tolerance and anergy. Over the past several years, a large number of molecules have been identified that function as second signals following TCR engagement, and many have been revealed to be negative costimulatory molecules, which dampen T-cell activation and regulate immune tolerance. Some have been shown to be upregulated in the tumour microenvironment and have become potential targets for augmenting anti-tumour immunity (Sharpe, 2009).