BLOCKADE OF BOTH L-SELECTIN AND ALPHA(4) INTEGRINS ABROGATES NAIVE CD4 CELL TRAFFICKING AND RESPONSES IN GUT-ASSOCIATED LYMPHOID ORGANS

The recirculation of naive lymphocytes from blood to lymph that is ini tiated in high endothelial venules (HEV) of secondary lymphoid organs such as lymph nodes and Peyer's patches (PP) is regulated by multiple interactions of adhesion receptor/counter-receptor pairs involving bot h selectins and integrins. We showed previously that blocking of only L-selectin is sufficient to ablate trafficking of naive CD4 cells and the development of their responses in peripheral lymph nodes but not i n PP where alpha(4)beta(7) integrins are thought to primarily regulate entry. However, although antibody to alpha(4) integrins partially inh ibited homing of naive CD4 cells to PP and not to lymph nodes, there w as no effect on the development primary responses in these tissues or spleens. Since previous studies indicate that both alpha(4)beta(7) int egrins and L-selectin regulate adhesion of naive cells to PP HEV, we e xamined the effect a blockade of bath adhesion pathways on the recircu lation of naive CD4 cells. There was no detectable homing of naive CD4 cells to PP or lymph nodes when interactions with both receptors were inhibited, resulting in a profound depletion of naive CD4 cells and l oss of antigen responses in these sites. In contrast, increased number s of naive CD4 cells and responses of higher magnitude were found in t he spleen. The results demonstrate recirculation of naive CD4 cells th rough tissues where entry is controlled through HEV is essential for t he local generation of primary responses.