Abstract
Abstract The development of T cell memory from naïve precursors is a complex process influenced by molecular cues received during T cell activation and differentiation. In the present study, we describe a novel role for the chemokine receptors CCR5 and CXCR3 in regulating effector CD8 T cell contraction and memory generation following influenza virus infection. Using mixed bone marrow chimeras, we find that Ccr5-/- Cxcr3-/- cells show markedly decreased contraction following viral clearance, leading to the establishment of massive numbers of memory CD8 T cells. Ccr5-/- Cxcr3-/- cells show preferential localization to the non-inflamed interstitial spaces of the infected lung, which coincides with reduced expression of the activation marker CD69 and the rapid appearance of CD127hi KLRG1lo memory precursor cells after viral clearance. Importantly, influenza-specific effector Ccr5-/- Cxcr3-/- CD8 T cells in the lung could be activated in vivo by the addition of exogenous antigen, which restored effector T cell contraction and significantly reduced memory T cell generation following viral clearance. Together, the data support a model of memory CD8 T cell generation where the chemokine-directed localization of T cells within infected tissues regulates antigen encounter and controls the extent of CD8 T cell activation and differentiation, which ultimately regulates effector versus memory cell-fate decisions.
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