Chemokine Signatures of Pathogen-Specific T Cells II: Memory T Cells in Acute and Chronic Infection

Abstract

Pathogen-specific memory T cells (T_M) contribute to enhanced immune protection under conditions of reinfection, and their effective recruitment into a recall response relies, in part, on cues imparted by chemokines that coordinate their spatiotemporal positioning. An integrated perspective, however, needs to consider T_M as a potentially relevant chemokine source themselves. In this study, we employed a comprehensive transcriptional/translational profiling strategy to delineate the identities, expression patterns, and dynamic regulation of chemokines produced by murine pathogen-specific T_M. CD8⁺T_M, and to a lesser extent CD4⁺T_M, are a prodigious source for six select chemokines (CCL1/3/4/5, CCL9/10, and XCL1) that collectively constitute a prominent and largely invariant signature across acute and chronic infections. Notably, constitutive CCL5 expression by CD8⁺T_M serves as a unique functional imprint of prior antigenic experience; induced CCL1 production identifies highly polyfunctional CD8⁺ and CD4⁺T_M subsets; long-term CD8⁺T_M maintenance is associated with a pronounced increase of XCL1 production capacity; chemokines dominate the earliest stages of the CD8⁺T_M recall response because of expeditious synthesis/secretion kinetics (CCL3/4/5) and low activation thresholds (CCL1/3/4/5/XCL1); and T_M chemokine profiles modulated by persisting viral Ags exhibit both discrete functional deficits and a notable surplus. Nevertheless, recall responses and partial virus control in chronic infection appear little affected by the absence of major T_M chemokines. Although specific contributions of T_M-derived chemokines to enhanced immune protection therefore remain to be elucidated in other experimental scenarios, the ready visualization of T_M chemokine-expression patterns permits a detailed stratification of T_M functionalities that may be correlated with differentiation status, protective capacities, and potential fates.