Unifying model for CLL surveillance by iNKT cells. (A) Stable disease correlates with absent or low CD1d CLL expression by CLL cells. In this situation, iNKT cells maintain normal frequencies and functions and the capability to constrain NLCs through a CD1d-cognate interaction, which has a negative impact on CLL survival. (B) Progressing disease correlates with high CD1d expression by CLL cells. In this situation, iNKT cells are persistently hyperstimulated by CLL cells in an antigen (Ag)-dependent fashion, leading to their exhaustion. As a result, iNKT cells no longer control NLCs, which can provide unconstrained support for CLL cell survival and proliferation.