CD1b-autoreactive T cells recognize phospholipid antigens and contribute to antitumor immunity against a CD1b⁺ T cell lymphoma

Adoptive immunotherapy for cancer treatment is an emerging field of study. Till now, several tumor-derived, peptide-specific T cell responses have been harnessed for treating cancers. However, the contribution of lipid-specific T cells in tumor immunity has been understudied. CD1 molecules, which present self- and foreign lipid antigens to T cells, are divided into group 1 (CD1a, CD1b, and CD1c) and group 2 (CD1d). Although the role of CD1d-restricted natural killer T cells (NKT) in several tumor models has been well established, the contribution of group 1 CD1-restricted T cells in tumor immunity remains obscure due to the lack of group 1 CD1 expression in mice. In this study, we used a double transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg) and a CD1b-restricted, self-lipid reactive T cell receptor (HJ1Tg) to study the potential role of group 1 CD1-restricted autoreactive T cells in antitumor response. We found that HJ1 T cells recognized phospholipids and responded more potently to lipid extracted from tumor cells than the equivalent amount of lipids extracted from normal cells. Additionally, the autoreactivity of HJ1 T cells was enhanced upon treatment with various intracellular toll-like receptor (TLR) agonists, including CpG oligodeoxynucleotides (ODN), R848, and poly (I:C). Interestingly, the adoptive transfer of HJ1 T cells conferred protection against the CD1b-transfected murine T cell lymphoma (RMA-S/CD1b) and CpG ODN enhanced the antitumor effect. Thus, this study, for the first time, demonstrates the antitumor potential of CD1b-autoreactive T cells and their potential use in adoptive immunotherapy.