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This process of prolific expansion is tightly regulated to quickly provide a robust pool of pathogen-fighting T cells, yet also limit excessive expansion to prevent inadvertent damage to host tissues. Restimulation-dependent pro-growth and pro-death signals help regulate this delicate balance of T cell expansion to maintain both host and T cell homeostasis. We have discovered that NDRG3 is a critical determinant of whether T cells proliferate or undergo apoptosis during repetitive restimulation under antigen-driven T cell expansion. CD8+ T cells lacking NDRG3 exhibit severely impaired expansion in vivo in response to both viral infections and tumor challenges. We show that NDRG3 is essential for T cell survival during antigen restimulation by protecting T cells from restimulation-induced cell death (RICD), while it has only a marginal impact on T cell survival in contexts with limited antigen restimulation. Mechanistically, NDRG3 safeguards repetitively stimulated T cells from RICD by constraining FAS-mediated pro-death signaling through caspase-8. Furthermore, NDRG3 overexpression enhanced T cell infiltration into tumors, improving their tumor-controlling capacity. Collectively, these findings establish NDRG3 as a novel, indispensable regulator of T cell responses to foreign challenges. Additionally, this work identifies NDRG3 as a previously undescribed regulator of RICD in T cells and reveals NDRG3 as a potential target for autoimmune disorders and chimeric antigen receptor T cell treatment for cancer.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag070","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T07:40:31Z","timestamp":1778830831000},"source":"Crossref","is-referenced-by-count":0,"title":["NDRG3 is essential for sustaining antigen-driven T cell responses by protecting against restimulation-induced cell death"],"prefix":"10.1093","volume":"215","author":[{"given":"Brian J","family":"Stack","sequence":"first","affiliation":[{"name":"NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies , La Jolla, CA,","place":["United States"]},{"name":"Biological Sciences Graduate Program, University of California San Diego , La Jolla, CA,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan M","family":"Kaech","sequence":"additional","affiliation":[{"name":"NOMIS Center for Immunobiology and Microbial Pathogenesis, Salk Institute for Biological Studies , La Jolla, CA,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026051503402641800_vkag070-B1","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1038\/nri3307","article-title":"Transcriptional control of effector and memory CD8+ T cell differentiation","volume":"12","author":"Kaech","year":"2012","journal-title":"Nat Rev Immunol"},{"key":"2026051503402641800_vkag070-B2","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/j.coi.2010.02.013","article-title":"Inflammatory cytokines as a third signal for T cell activation","volume":"22","author":"Curtsinger","year":"2010","journal-title":"Curr Opin Immunol"},{"key":"2026051503402641800_vkag070-B3","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/S1074-7613(02)00323-0","article-title":"The CD28 signaling pathway regulates glucose metabolism","volume":"16","author":"Frauwirth","year":"2002","journal-title":"Immunity"},{"key":"2026051503402641800_vkag070-B4","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1146\/annurev.immunol.15.1.707","article-title":"Transcription factors of the NFAT family: regulation and function","volume":"15","author":"Rao","year":"1997","journal-title":"Annu Rev Immunol"},{"key":"2026051503402641800_vkag070-B5","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1128\/JVI.01459-06","article-title":"Quantitating the magnitude of the lymphocytic choriomeningitis virus-specific CD8 T-cell response: it is even bigger than we thought","volume":"81","author":"Masopust","year":"2007","journal-title":"J Virol"},{"key":"2026051503402641800_vkag070-B6","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1084\/jem.20001021","article-title":"Estimating the precursor frequency of naive antigen-specific CD8 T cells","volume":"195","author":"Blattman","year":"2002","journal-title":"J Exp Med"},{"key":"2026051503402641800_vkag070-B7","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1111\/j.1600-065X.2010.00917.x","article-title":"The power and the promise of restimulation-induced cell death in human immune diseases","volume":"236","author":"Snow","year":"2010","journal-title":"Immunol Rev"},{"key":"2026051503402641800_vkag070-B8","first-page":"289","article-title":"IL-2 addiction: withdrawal of growth factor activates a suicide program in dependent T cells","volume":"5","author":"Duke","year":"1986","journal-title":"Lymphokine Res"},{"key":"2026051503402641800_vkag070-B9","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1084\/jem.165.1.173","article-title":"Cell growth cycle block of T cell hybridomas upon activation with antigen","volume":"165","author":"Ashwell","year":"1987","journal-title":"J Exp Med"},{"key":"2026051503402641800_vkag070-B10","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/353858a0","article-title":"Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis","volume":"353","author":"Lenardo","year":"1991","journal-title":"Nature"},{"key":"2026051503402641800_vkag070-B11","doi-asserted-by":"crossref","first-page":"1281137","DOI":"10.3389\/fceld.2023.1281137","article-title":"Molecular and temporal control of restimulation-induced cell death (RICD) in T lymphocytes","volume":"2","author":"Lee","year":"2023","journal-title":"Front. 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