Wide variations exist in human lifespan, health status across ages, and susceptibility to infectious diseases. This study hypothesizes that optimal immune resilience (IR), defined as the capacity to preserve or rapidly restore immune functions, contributes significantly to these differences. Using two peripheral blood metrics – CD8+/CD4+ T-cell balance and gene expression signatures – IR levels were assessed in nearly 50,000 individuals. Results indicate that optimal IR is associated with lower risks of various infections and cancers, improved survival during COVID-19 and sepsis, and increased longevity. IR degradation is potentially reversible by reducing inflammatory stress. Optimal IR is more common in females and linked to a specific immunocompetence-inflammation balance.

Sunil K Ahuja, Muthu Saravanan Manoharan, Grace C Lee, Lyle R McKinnon, Justin A Meunier, Maristella Steri, Nathan Harper, Edoardo Fiorillo, Alisha M Smith, Marcos I Restrepo, Anne P Branum, Matthew J Bottomley, Valeria Orrù, Fabio Jimenez, Andrew Carrillo, Lavanya Pandranki, Caitlyn A Winter, Lauryn A Winter, Alvaro A Gaitan, Alvaro G Moreira, Elizabeth A Walter, Guido Silvestri, Christopher L King, Yong Tang Zheng, Hong Yi Zheng, Joshua Kimani, T Blake Ball, Francis A Plummer, Keith R Fowke, Paul N Harden, Kathryn J Wood, Martin T Ferris, Jennifer M Lund, Mark T Heise, Nigel Garrett, Kristen R Canady, Salim S Abdool Karim, Susan J Little, Sara Gianella, Davey M Smith, Scott Letendre, Douglas D Richman, Francesco Cucca, Hanh Trinh, Sandra Sanchez Reilly, Joan M Hecht, Jose A Cadena Zuluaga, Antonio Anzueto, Jacqueline A Pugh, South Texas Veterans Health Care System COVID 19 team, Brian K Agan, Robert Root Bernstein, Robert A Clark, Jason F Okulicz, Weijing He