biostudies-literatureGago da Graca CMedical Research Councileadn1945https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617396biostudies-literatureUnknown10(103)Stem-like T cells are attractive immunotherapeutic targets in patients with cancer given their ability to proliferate and differentiate into effector progeny. Thus, identifying T cells with enhanced stemness and understanding their developmental requirements are of broad clinical and therapeutic interest. Here, we demonstrate that during acute infection, the transcriptional regulator inhibitor of DNA binding 3 (ID3) identifies stem-like T cells that are uniquely adapted to generate precursors of exhausted T (Tpex) cells in response to chronic infection or cancer. Expression of ID3 itself enables Tpex cells to sustain T cell responses in chronic infection or cancer, whereas loss of ID3 results in impaired maintenance of CD8 T cell immunity. Furthermore, we demonstrate that interleukin-1 (IL-1) family members, including IL-36β and IL-18, promote the generation of ID3⁺ T cells that mediate superior tumor control. Overall, we identify ID3 as a common denominator of stem-like T cells in both acute and chronic infections that is specifically required to sustain T cell responses to chronic stimulation.Science immunologyStem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression.PMC7617396MR/V009052/1Kallies AShen JSu CHBending DSchroder JChisanga DGabriel SSNguyen MTShi WSheikh AACluse LASingh JWen LVasanthakumar AMackay LKPark SLUtzschneider DTSeow JCui WJohnstone RWPoch ANewman DMBurn TNLi STsui CGago da Graca CZhang YRausch LVon Scheidt BfalseStem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression.Stem-like T cells are attractive immunotherapeutic targets in patients with cancer given their ability to proliferate and differentiate into effector progeny. Thus, identifying T cells with enhanced stemness and understanding their developmental requirements are of broad clinical and therapeutic interest. Here, we demonstrate that during acute infection, the transcriptional regulator inhibitor of DNA binding 3 (ID3) identifies stem-like T cells that are uniquely adapted to generate precursors of exhausted T (Tpex) cells in response to chronic infection or cancer. Expression of ID3 itself enables Tpex cells to sustain T cell responses in chronic infection or cancer, whereas loss of ID3 results in impaired maintenance of CD8 T cell immunity. Furthermore, we demonstrate that interleukin-1 (IL-1) family members, including IL-36β and IL-18, promote the generation of ID3⁺ T cells that mediate superior tumor control. Overall, we identify ID3 as a common denominator of stem-like T cells in both acute and chronic infections that is specifically required to sustain T cell responses to chronic stimulation.2025-01-01T00:00:00Z2025 Jan2025-04-04T01:45:56.472Z2025-04-04T01:45:56.472ZS-EPMC76173963988898110.1126/sciimmunol.adn1945