ID3 and c-Kit define the stem-like potential of T cells and their response to chronic infection and cancer

Memory CD8+ T cells and precursors of exhausted T (Tpex) cells are important therapeutic targets due to their stem-like potential that allows them to self-renew while also giving rise to large numbers of effector T cells that can provide protection from infection or uncontrolled tumor growth. Identifying T cells with stem-like potential and understanding their molecular regulation is therefore critical to improve a wide range of T cell-focused therapies ranging from vaccination to checkpoint inhibitor and chimeric antigen receptor T cell therapies. Here, we identify memory T cells based on expression of the transcriptional regulator ID3 while lacking expression of the chemokine receptor CXCR6 with superior stem-like potential to sustain T cell responses during chronic infection. Mechanistically, ID3 regulated a transcriptional network including Myb, Sell and cKit that promoted T cell stemness that was specifically required during ongoing T cell receptor stimulation. T cells lacking ID3 were unable to sustain a long-term response to chronic infection but capable of efficiently responding to acute infection. Overall, we identify a critical role for ID3 in promoting functional and long-lasting T cell responses specifically to chronic infections and highlight ID3-expressing stem-like memory T cells as a promising immunotherapeutic target to improve immune responses in chronic infections or tumors.