Chemokine guidance of central memory T cells is critical for anti-viral recall responses in lymph nodes (44.8)

Abstract

Abstract A defining feature of vertebrate immunity is the capacity to acquire immunological memory against recurrent pathogens. During a viral infection, virus-specific memory T cells accelerate anti-viral effector responses and promote faster viral clearance than naive T cells (Tn), but the mechanism for this enhanced protection has been unclear. To address this question, mice were subcutaneously injected with either live virus or antigen (Ag)-pulsed dendritic cells (DCs) and the response of Tn and central memory T cells (Tcm) was visualized in draining lymph nodes (LNs). Upon challenge with Ag-pulsed DCs that carried Ag to deep T cell area, Tn and Tcm interacted similarly with Ag-pulsed DCs. Upon viral challenge, however, Tcm relocalized much more efficiently than Tn toward regions of initial viral infection in the medullary, interfollicular and subcapsular area. This redistribution depended upon chemokine receptor CXCR3 and occured in two sequential steps driven by distinct cytokines and chemokines. Initially, type I interferon-induced CXCL10 promoted peripheralization of Tcm independently of Ag specificity. Subsequently, upon encountering cognate Ag, Tcm produced interferon-γ, which in turn induced a second CXCR3 ligand, CXCL9. Upon viral infection, in vivo recall responses by CXCR3-deficient Tcm were markedly compromised, whereas in vitro responses were intact, suggesting that CXCR3-dependent Tcm relocalization is essential for intranodal anti-viral Tcm function.