Effector Function-Deficient Memory CD8+ T Cells Clonally Expand in the Liver and Give Rise to Peripheral Memory CD8+ T Cells

摘要

Upon adoptive transfer into histocompatible mice, naive CD8+ T cells stimulated ex vivo by TCR+IL-4 turn into long-lived functional memory cells. The liver contains a large number of so formed memory CD8+ T cells, referred to as liver memory T cells (Tlm) in the form of cell clusters. The CD62Llow expression and nonlymphoid tissue distribution of Tlm cells are similar to effector memory (Tem) cells, yet their deficient cytotoxicity and IFN-γ inducibility are unlike Tem cells. Adoptive transfer of admixtures of TCR+IL-4–activated Vβ8+ and Vβ5+ CD8+ T cells into congenic hosts reveals Tlm clusters that are composed of all Vβ5+ or Vβ8+, not mixed Vβ5+/Vβ8+ cells, indicating that Tlm clusters are formed by clonal expansion. Clonally expanded CD8+ T cell clusters are also seen in the liver of Listeria monocytogenes -immune mice. Tlm clusters closely associate with hepatic stellate cells and their formation is IL-15/IL-15R–dependent. CD62Llow TLM cells can home to the liver and secondary lymphoid tissues, remain CD62Llow, or acquire central memory (Tcm)-characteristic CD62Lhi expression. Our findings show the liver as a major site of CD8+ memory T cell growth and that Tlm cells contribute to the pool of peripheral memory cells. These previously unappreciated Tlm characteristics indicate the inadequacy of the current Tem/Tcm classification scheme and help ongoing efforts aimed at establishing a unifying memory T cell development pathway. Lastly, our finding of Tlm clusters suggests caution against interpreting focal lymphocyte infiltration in clinical settings as pathology and not normal physiology.