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

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 (T-LM) in the form of cell clusters. The CD62L(low) expression and nonlymphoid tissue distribution of T-LM cells are similar to effector memory (T-EM) cells, yet their deficient cytotoxicity and IFN-gamma inducibility are unlike T-EM cells. Adoptive transfer of admixtures of TCR+IL-4-activated V beta 8(+) and V beta 5(+) CD8(+) T cells into congenic hosts reveals T-LM clusters that are composed of all V beta 5(+) or V beta 8(+), not mixed V beta 5(+)/V beta 8(+) cells, indicating that T-LM clusters are formed by clonal expansion. Clonally expanded CD8(+) T cell clusters are also seen in the liver of Listeria monocytogenes-immune mice. T-LM clusters closely associate with hepatic stellate cells and their formation is IL-15/IL-15R-dependent. CD62L(low) T-LM cells can home to the liver and secondary lymphoid tissues, remain CD62L(low), or acquire central memory (T-CM)-characteristic CD62L(hi) expression. Our findings show the liver as a major site of CD8(+) memory T cell growth and that T-LM cells contribute to the pool of peripheral memory cells. These previously unappreciated T-LM characteristics indicate the inadequacy of the current T-EM/T-CM classification scheme and help ongoing efforts aimed at establishing a unifying memory T cell development pathway. Lastly, our finding of T-LM clusters suggests caution against interpreting focal lymphocyte infiltration in clinical settings as pathology and not normal physiology. The Journal of Immunology, 2010, 185: 7498-7506.