THE AMERICAN JOURNAL OF ANATOMY zyx 170:391-405 (1984) Localization of Lymphocyte Subpopulations in Peripheral Lymphoid Organs: Directed Lymphocyte Migration and Segregation Into Specific Microenvironments ROBERT V. ROUSE, ROGER A. REICHERT, W. MICHAEL GALLATIN, IRVING L. WEISSMAN, zyxwvu AND EUGENE C. BUTCHER zyxw Departments of Pathology, Stanford Uniuersity Medical Center, Stanford, California, and Veterans Administration Medical Center, Palo Alto, California ABSTRACT The distribution of lymphocytes in the peripheral lymphoid organs is controlled by recirculatory and microenvironmental factors. Specific interactions between recirculating lymphocytes and high endothelial venules in various lymphoid organs determine the presence and proportions of the various lymphoid sets and subsets in those organs. Separate endothelial deter- minants on peripheral node and Peyer’s patch endothelium along with comple- mentary lymphocyte receptors mediate this organ specificity. B and T cells also exhibit nonrandom organization within lymphoid tissues; after entry via high endothelial venules they segregate into their respective domains, which appear to be determined by distinct types of nonlymphoid stromal cells. Anti- genic stimulation results in changes in lymphocyte phenotype as well as in the lymphoid microenvironment. The response to most complex antigens is the formation of germinal centers (GC) composed primarily of proliferating B cells; the phenotype of the few T cells therein is supportive of the GC as a site of B- T interaction. The phenotype of the B cells in GCs suggest a role for GCs in immunoglobulin class switching and the determination of subsequent homing specificity. LYMPHOCYTE MIGRATION AND LYMPHOID ARCHITECTURE The major peripheral lymphoid organs (lymph nodes, splenic white pulp, and Pey- er’s patches) are the principal sites of congre- gation of mature lymphocytes. These lym- phocytes make up the bulk of these organs. Their tissue distribution is not random, how- ever, but seems to reflect the particular de- mands placed upon the function of each organ. B cells, responsible for humoral im- munity, make up more than two-thirds of the lymphoid population of Peyer’s patches and the spleen. In contrast, more than two-thirds of peripheral node lymphocytes are T cells, the principal effectors of cellular immunity (Stevens et al., 1982).Such nonrandom distri- butions are exhibited by plasma cells as well: IgA plasma cells are found in and near mu- cosal surfaces, whereas IgG and IgM plasma cells are distributed predominantly in non- mucosal regions. How are these consistent differences in the distributions of lymphocyte sets and subsets established and main- tained? Some cells are generated zy in situ by cell division, particularly after antigenic stimulation; but this cannot be the major mechanism as most small lymphocytes are not long term residents of any one peripheral lymphoid site but instead recirculate throughout the body. Most mature, small lymphocytes are con- stantly circulating, leaving lymphoid organs in the efferent lymph, draining via the tho- racic duct into the blood and then returning to another peripheral lymphoid organ (Go- wans and Knight, 1964).Not all lymphocytes recirculate at the same rate-studies in ro- dents have shown that on average B cells take longer than T cells to reappear in tho- Received March 14, 1984. Accepted March zyx 23, 1984. zy 0 1984 ALAN R. LISS, INC.