biostudies-literatureGomez de Las Heras MMEuropean Research Councileadv0985https://www.ebi.ac.uk/biostudies/studies/S-EPMC7618201biostudies-literatureUnknown10(110)Healthy aging relies on a symbiotic host-microbiota relationship. The age-associated decline of the immune system can pose a threat to this delicate equilibrium. In this work, we investigated how the functional deterioration of T cells can affect host-microbiota symbiosis and gut barrier integrity and the implications of this deterioration for inflammaging, senescence, and health decline. Using the <i>Tfam</i>^fl/fl<i>Cd4</i>^Cre mouse model, we found that T cell failure compromised gut immunity leading to a decrease in T follicular cells and regulatory T cells (T_reg cells) and an accumulation of highly proinflammatory and cytotoxic T cells. These alterations were associated with intestinal barrier disruption and gut dysbiosis. Microbiota depletion or adoptive transfer of total CD4 T cells or a T_reg cell-enriched pool prevented gut barrier dysfunction and mitigated premature inflammaging and senescence, ultimately enhancing the health span in this mouse model. Thus, a competent CD4 T cell compartment is critical to ensure healthier aging by promoting host-microbiota mutualism and gut barrier integrity.Science immunologyCD4 T cell therapy counteracts inflammaging and senescence by preserving gut barrier integrity.PMC7618201101044248Fernandez-Almeida AFrancos-Quijorna IAranda JFDias-Almeida JSimo CNunez GDelgado-Pulido SGalvez-Castano MIGomez de Las Heras MMMittelbrunn MGarcia-Canas VEscrig-Larena JIPerez-Manrique MSoto-Heredero GGabande-Rodriguez EInohara NCarrasco EBlanco EMfalseCD4 T cell therapy counteracts inflammaging and senescence by preserving gut barrier integrity.Healthy aging relies on a symbiotic host-microbiota relationship. The age-associated decline of the immune system can pose a threat to this delicate equilibrium. In this work, we investigated how the functional deterioration of T cells can affect host-microbiota symbiosis and gut barrier integrity and the implications of this deterioration for inflammaging, senescence, and health decline. Using the <i>Tfam</i>^fl/fl<i>Cd4</i>^Cre mouse model, we found that T cell failure compromised gut immunity leading to a decrease in T follicular cells and regulatory T cells (T_reg cells) and an accumulation of highly proinflammatory and cytotoxic T cells. These alterations were associated with intestinal barrier disruption and gut dysbiosis. Microbiota depletion or adoptive transfer of total CD4 T cells or a T_reg cell-enriched pool prevented gut barrier dysfunction and mitigated premature inflammaging and senescence, ultimately enhancing the health span in this mouse model. Thus, a competent CD4 T cell compartment is critical to ensure healthier aging by promoting host-microbiota mutualism and gut barrier integrity.2025-01-01T00:00:00Z2025 Aug2026-06-04T04:49:23.278Z2026-05-05T03:12:38.102ZS-EPMC76182014074903510.1126/sciimmunol.adv0985