Memory CD8⁺T cells mediate early pathogen-specific protection via localized delivery of chemokines and IFNγ to clusters of monocytes

While cognate antigen drives clonal expansion of memory CD8+ T (CD8+ TM) cells to achieve sterilizing immunity in immunized hosts, not much is known on how cognate antigen contributes to early protection before clonal expansion occurs. Here, using distinct models of immunization, we establish that cognate antigen recognition by CD8+ TM cells on dendritic cells initiates their rapid and coordinated production of a burst of CCL3, CCL4, and XCL1 chemokines under the transcriptional control of interferon (IFN) regulatory factor 4. Using intravital microscopy imaging, we reveal that CD8+ TM cells undergo antigen-dependent arrest in splenic red pulp clusters of CCR2+Ly6C+ monocytes to which they deliver IFNγ and chemokines. IFNγ enables chemokine-induced microbicidal activities in monocytes for protection. Thus, rapid and effective CD8+ TM cell responses require spatially and temporally coordinated events that quickly restrict microbial pathogen growth through the local delivery of activating chemokines to CCR2+Ly6C+ monocytes.