Antigen-Independent Differentiation and Maintenance of Effector-like Resident Memory T Cells in Tissues

TLDR

Effector memory CD8⁺ T cells (TEM) require prolonged antigen stimulation for differentiation, yet it is unclear whether tissue‑resident effector memory T cells (TRM) use similar pathways, despite TRM in the small intestine exhibiting a long‑lived effector‑like phenotype that suggests persistent antigen exposure. The study aimed to identify the antigenic cues and requirements that drive differentiation and maintenance of intestinal TRM, including local stimulation by cognate or cross‑reactive antigens from pathogens, microbiota, or diet. Contrary to expectations, intestinal TRM differentiation and maintenance do not depend on prolonged cognate antigen stimulation; instead, cytokine‑driven expression of CD69 and CD103—particularly TGF‑β–mediated CD103—supports a location‑dependent, antigen‑independent pathway that sustains long‑lived effector‑like TRM across multiple tissues.

Abstract

Abstract Differentiation and maintenance of recirculating effector memory CD8 T cells (TEM) depends on prolonged cognate Ag stimulation. Whether similar pathways of differentiation exist for recently identified tissue-resident effector memory T cells (TRM), which contribute to rapid local protection upon pathogen re-exposure, is unknown. Memory CD8αβ+ T cells within small intestine epithelium are well-characterized examples of TRM, and they maintain a long-lived effector-like phenotype that is highly suggestive of persistent Ag stimulation. This study sought to define the sources and requirements for prolonged Ag stimulation in programming this differentiation state, including local stimulation via cognate or cross-reactive Ags derived from pathogens, microbial flora, or dietary proteins. Contrary to expectations, we found that prolonged cognate Ag stimulation was dispensable for intestinal TRM ontogeny. In fact, chronic antigenic stimulation skewed differentiation away from the canonical intestinal T cell phenotype. Resident memory signatures, CD69 and CD103, were expressed in many nonlymphoid tissues including intestine, stomach, kidney, reproductive tract, pancreas, brain, heart, and salivary gland and could be driven by cytokines. Moreover, TGF-β–driven CD103 expression was required for TRM maintenance within intestinal epithelium in vivo. Thus, induction and maintenance of long-lived effector-like intestinal TRM differed from classic models of TEM ontogeny and were programmed through a novel location-dependent pathway that was required for the persistence of local immunological memory.