Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance

Memory CD8 T cells protect against intracellular pathogens by scanning host cell surfaces; thus, infection detection rates depend on memory cell number and distribution. Population analyses rely on cell isolation from whole organs, and interpretation is predicated on presumptions of near complete cell recovery. Paradigmatically, memory is parsed into central, effector, and resident subsets, ostensibly defined by immunosurveillance patterns but in practice identified by phenotypic markers. Because isolation methods ultimately inform models of memory T cell differentiation, protection, and vaccine translation, we tested their validity via parabiosis and quantitative immunofluorescence microscopy of a mouse memory CD8 T cell population. We report three major findings: lymphocyte isolation fails to recover most cells and biases against certain subsets, residents greatly outnumber recirculating cells within non-lymphoid tissues, and memory subset homing to inflammation does not conform to previously hypothesized migration patterns. These results indicate that most host cells are surveyed for reinfection by segregated residents rather than by recirculating cells that migrate throughout the blood and body. [Display omitted] •Isolations underestimate memory CD8 T cells in nonlymphoid tissues (NLT)•Together, memory CD8 T cells in NLTs and blood outnumber those in lymphoid organs•Without inflammation, TCM and TEM surveillance of nonlymphoid tissues is minimal•Each NLT is primarily surveyed by discrete resident populations that remain local Most anatomic compartments, including solid organs and vascular spaces, are patrolled by resident populations of memory CD8 T cells that stay local. The number of residents are underestimated by standard immunologic assays and indicate that immunosurveillance by CD8 T cells is highly regionalized.