Effect of IL-4 on the development and function of memory-like CD8 T cells in the peripheral lymphoid tissues

Unlike conventional T cells, innate CD8 T cells develop a memory-like phenotype in the thymus and immediately respond upon antigen stimulation, similar to memory T cells. The development of innate CD8 T cells in the thymus is known to require IL-4, which upregulates Eomesodermin (Eomes). These features are similar to that of virtual memory CD8 T cells and IL-4-induced memory-like CD8 T cells generated in the peripheral tissues. However, the relationship between these cell types has not been clearly documented. In the present study, IL-4-induced memory-like CD8 T cells generated in the peripheral tissues were compared with innate CD8 T cells in terms of phenotype and function. When an IL-4/anti-IL-4 antibody complex (IL-4C) was injected into C57BL/6 mice daily for 7 days, the Eomes^hiCXCR3^＋ CD8 T cell population was markedly increased in the peripheral lymphoid organs and blood. These cells were generated from naïve CD8 T cells or accumulated via the expansion of pre-existing CD44^hiCXCR3^＋ CD8 T cells. Initially, the majority of these CXCR3^＋ CD8 T cells expressed low levels of CD44, which was followed by the conversion to the CD44^hi phenotype. This conversion was associated with the acquisition of enhanced ef- fector function. After discontinuation of IL-4C treatment, Eomes expression levels gradually decreased in CXCR3^＋ CD8 T cells. Taken together, the results of this study demonstrate that IL-4-induced memory-like CD8 T cells generated in the peripheral lymphoid tissues are phenotypi-cally and functionally similar to the innate CD8 T cells generated in the thymus.