Intestinal resident effector-memory CD4 T cells on the adaptive-innate spectrum comprise IL-18 reactivity and adaptive CMV specificity.

The human tissue-resident T cell pool consists of a diverse array of conventional adaptive as well as unconventional invariant T cells that populate barrier sites and carefully balance immune defense in the context of microbial exposure. Here, we investigated the tissue-resident CD4 T cell compartment across donor-matched lymphoid and nonlymphoid tissues and uncovered a population enriched primarily in the ileum and liver displaying a rich polyfunctional profile with diverse T helper 1/17/22 characteristics. These CD4 T cells were highly responsive, susceptible to innate cytokine-driven activation, and identified by CD161 and CD56 coexpression. Their transcriptional and protein expression profile included innate-like effector features including NKp80, NKG2D, NKG7, as well as granzyme K, and exhibited characteristics of tissue residence, persistence, and barrier repair, and they were depleted in the colon of patients with inflammatory bowel disease. Notably, the CD161+ CD56+ CD4 T cell pool was expanded in cytomegalovirus (CMV)-seropositive individuals and enriched in CMV-specific T cell receptors and responses. Together, we identify a potent effector-memory CD4 T cell subset resident in the gastrointestinal tract and liver, defined by enhanced innateness and enriched in CMV-specificity.