Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection
Authors: Ahuja Sunil K. , Manoharan Muthu Saravanan , Lee Grace C. , McKinnon Lyle R. , Meunier Justin A. , Steri Maristella , Harper Nathan , Fiorillo Edoardo , Smith Alisha M. , Restrepo Marcos I. , Branum Anne P. , Bottomley Matthew J. , Orrù Valeria , Jimenez Fabio , Carrillo Andrew , Pandranki Lavanya , Winter Caitlyn A. , Winter Lauryn A. , Gaitan Alvaro A. , Moreira Alvaro G. , Walter Elizabeth A. , Silvestri Guido , King Christopher L. , Zheng Yong-Tang , Zheng Hong-Yi , Kimani Joshua , Blake Ball T. , Plummer Francis A. , Fowke Keith R. , Harden Paul N. , Wood Kathryn J. , Ferris Martin T. , Lund Jennifer M. , Heise Mark T. , Garrett Nigel , Canady Kristen R. , Abdool Karim Salim S. , Little Susan J. , Gianella Sara , Smith Davey M. , Letendre Scott , Richman Douglas D. , Cucca Francesco , Trinh Hanh , Sanchez-Reilly Sandra , Hecht Joan M. , Cadena Zuluaga Jose A. , Anzueto Antonio , Pugh Jacqueline A. ,   South Texas Veterans Health Care System COVID-19 team, Abdalla Mohamed I. , Adams Sandra G. , Adebayo Yemi , Agnew Joseph , Ali Saleem , Anstead Gregory , Balmes Marichu , Barker Jennifer , Baruch-Bienen Deborah , Bible Velma , Birdwell Angela , Braddy Stacy , Bradford Stephen , Briggs Heather , Corral Judith M. , Dacus Jennifer J. , Danaher Patrick J. , DePaul Scott A. , Dickerson Jill , Doanne Jollynn , Ehsan Aamir , Elbel Samantha , Escalante Miguel , Escamilla Corina , Escamilla Valerie , Farrar Robert , Feldman David , Flores Debra , Flynn Julianne , Ford Delvina , Foy Joanna D. , Freeman Megan , Galley Samantha , Garcia Jessica , Garza Maritza , Gilman Sherraine , Goel Melanie , Gomez Jennifer , Goyal Varun K. , Grassmuck Sally , Grigsby Susan , Hanson Joshua , Harris Brande , Haywood Audrey , Hinojosa Cecilia , Ho Tony T. , Hopkins Teri , Horvath Lynn L. , Hussain Aneela N. , Jabur Ali , Jewell Pamela , Johnson Thomas B. , Lawler Austin C. , Lee Monica , Lester Chadwick S. , Levine Stephanie M. , Lewis Haidee V. , Louder Angel , Mainor Charmaine , Maldonado Rachel , Martinez Celida , Martinez Yvette , Maselli Diego , Mata Chloe , McElligott Neil , Medlin Laura , Mireles Myra , Moreno Joanna , Morneau Kathleen , Muetz Julie , Munro Samuel B. , Murray Charlotte , Nambiar Anoop , Nassery Daniel , Nathanson Robert , Oakman Kimberly , O’Rorke Jane , Padgett Cheryl , Pascual-Guardia Sergi , Patterson Marisa , Perez Graciela L. , Perez Rogelio , Perez Rogelio , Phillips Robert E. , Polk Patrick B. , Pomager Michael A. , Preston Kristy J. , Proud Kevin C. , Rangel Michelle , Ratcliffe Temple A. , Reichelderfer Renee L. , Renz Evan M. , Ross Jeanette , Rudd Teresa , Sanchez Maria E. , Sanders Tammy , Schindler Kevin C. , Schmit David , Sehgal Raj T. , Solorzano Claudio , Soni Nilam , Tam Win S. , Tovar Edward J. , Trammell Velasquez Sadie A. , Tyler Anna R. , Vasquez Anjuli , Veloso Maria C. , Venticinque Steven G. , Villalpando Jorge A. , Villanueva Melissa , Villegas Lauren , Walker Megan , Wallace Andrew , Wallace Maria , Wang Emily , Wickizer Stephanie , Williamson Andreia , Yunes Andrea , Zentner Katharine H. , Agan Brian K. , Root-Bernstein Robert , Clark Robert A. , Okulicz Jason F. , He Weijing 
Published: June 2023

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.