CD8 T cells are crucial for the protection against tumors and intracellular pathogens via their ability to generate long-term memory. Memory T cells (TMem) are however not a homogenous population. Traditionally, blood-borne TMem have been sub-divided into central memory (TCM) and effector memory (TEM) cells based on different migration behaviors and cytotoxic potential.

We recently discovered the existence of a novel subset of CD8 TMem that has unique migratory properties and a superior homeostatic self-renewal capacity. The hitherto unrecognized memory CD8 T cell subset is characterized by intermediate expression levels of CX3CR1, while classical TCM were CX3CR1, and TEM were CX3CR1high. The fraction of CX3CR1int cells among antigen-experienced TMem was remarkably stable over the course of a year, while TEM gradually declined and TCM increased to be the largest subset by 10 months. Interestingly, CX3CR1int TMem had the highest proliferation rate of the three TMem subsets. While TCM and TEM were phenotypically stable over >10 weeks at steady state, CX3CR1int TMem not only self-renewed, but also gave rise to bonafide TCM. Consequently, CX3CR1int TMem contributed to the gradual increase in TCM.

The newly identified CX3CR1int TMem displayed unique migratory properties. Unlike CX3CR1high TEM, CX3CR1int gradually acquired lymph node homing capability. Moreover, parabiosis experiments and analysis of recirculating memory cells in thoracic duct lymph revealed that CX3CR1int TMem, not TEM, are the predominant T cell subset surveying non-lymphoid peripheral tissues.

Supported by a postdoctoral fellowship of the Cancer Research Institute Irvington Fellowship Program and a Rubicon fellowship (Netherlands Organization for Scientific Research, NWO) to CG, NIH T32 Training Grant in Hematology 5T32-HL07623-20 to EAM, NIH F31 grant CA171339 to SML, NIH T32 grant HL066987 to DA, the Ragon Institute of MGH, MIT and Harvard and NIH/NIAID RO1 AI069259, PO1 AI078897 and PO1 AI112521 to UHvA.

Citation Format: Carmen Gerlach, E. Ashley Moseman, Scott M. Loughhead, David Alvarez, Anthonie J. Zwijnenburg, Lisette Waanders, Rohit Garg, Juan C. de la Torre, Ulrich H. von Andrian. CX3CR1 distinguishes three distinct migratory memory CD8 T cell subsets [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A057.