The migratory behavior of murine CD4(+) cells of memory phenotype

Lymphocyte differentiation is connected with profound alterations in the migratory pattern of lymphocytes. Whereas naive cells predominantly recirculate through lymphoid tissues, activated lymphocytes acquire an increased preference for immigration into non-lymphoid tissues and a reduced capacity for recirculation via high endothelial venules (HEV). A variety of data had indicated that memory-related subpopulations of cells in man and sheep, classified by the low expression of the CD45RA isotype, also lack the capacity to recirculate via HEV. However, recent data in the rat called these results into question. We therefore analyzed the migration properties of murine CD4(+) T cell subpopulations defined by several markers used to distinguish memory from naive CD4(+) cells in mice, namely CD45RB, L-selectin and CD44. Our data clearly show that the majority of putative memory cells expressing either low levels of CD45RB, low levels of L-selectin or high levels of CD44 display a strongly reduced capacity for direct entry into lymphoid tissues, including the spleen, from the blood stream. The accumulation in peripheral lymph nodes is further reduced by treatment with anti-L-selectin antibody, which blocks their entry via HEV. This indicates that memory CD4(+) T cells are not excluded from crossing lymph node HEV, and that the numbers of cells entering the node via this route exceed the numbers entering via the afferent lymph, at least in the absence of local inflammation. Concomitantly, a strongly enhanced localization of cells of the memory phenotype is observed in lung and liver as compared with naive cells. Trafficking to specific sites such as skin or gut mucosa is not a prominent feature of the total population of memory cells. The trafficking to lung and liver and an increased ability to bind to dendritic cells, demonstrable in in vitro adhesion assays, suggest a more sessile phenotype of most memory cells. With respect to these properties, memory cells have a surprizing similarity to fully activated lymphocytes.