R A Reichert

Homing receptors and the control of lymphocyte migration

The traffic of lymphocytes is controlled in part by the selective interaction of circulating lymphocytes with specialized high endothelial venule (HEV) cells at sites of lymphocyte exit from the blood. At least three independent receptor systems are responsible for controlling lymphocyte traffic to different lymphoid organs or to sites of inflammation: one mediates lymphocyte interaction with HEV in peripheral lymph nodes, another in mucosa-associated lymphoid tissues, and a third in inflamed synovium. The receptors mediating lymphocyte recognition of HEV in different organs appear to be structurally related yet antigenically and functionally distinct 90 kD glycoproteins. Receptors for lymph node HEV can function as mammalian lectins, and probably interact with specific carbohydrate ligands on high endothelial cells. Mouse and human homing receptors share both antigenic and structural features, indicating a high conservation of lymphocyte-endothelial recognition systems during evolution. They play an essential part in the immune process by controlling lymphocyte traffic during B- and T-cell differentiation, and by segregating effector cells derived from stimulation in different tissues, thus simultaneously increasing the efficiency of organ-specific immune responses and decreasing possibilities for autoimmune crossreactions. Homing receptors are also expressed by many mouse and human lymphoid neoplasms, and appear to play a role in lymphoma metastasis. Related if not identical receptors are expressed by other leukocyte types, including polymorphonuclear leukocytes, monocytes, and large granular lymphocytes (natural killer cells). Thus lymphocyte homing receptors are members of a family of glycoprotein receptors for endothelium that control the extravasation of lymphocytes as well as other leukocytes, and help regulate both non-specific and specific immune responses in vivo.

A homing receptor-bearing cortical thymocyte subset: Implications for thymus cell migration and the nature of cortisone-resistant thymocytes

The thymus exports a selected subset of virgin T lymphocytes to the peripheral lymphoid organs. The mature phenotype of these thymus emigrants is similar to that of medullary thymocytes and has been cited as supporting a medullary rather than cortical exit site. Using the monoclonal antibody MEL-14, we identify a 1%-3% subpopulation of thymocytes that expresses high levels of a receptor molecule involved in lymphocyte homing to peripheral lymph nodes. We present evidence that these rare MEL-14hi thymocytes are predominantly of mature phenotype and represent the major source of thymus emigrants. Surprisingly, MEL-14hi thymocytes are exclusively cortical in location, although their mature phenotype may allow them to masquerade as medullary cells in conventional studies. We also demonstrate that unlike medullary thymocytes, many cortisone-resistant thymocytes (CRT) are MEL-14hi. Thus, in contrast to current dogma, CRT do not represent a sample of medullary thymocytes as they are found in situ and their level of immunocompetence does not necessarily reflect that of the medullary population. Our findings refute the hypothesis that phenotypically and functionally mature cells are restricted to the medulla, and support our proposition that most thymus emigrants are derived from the MEL-14hi cortical subset.

Surface Phenotype and Migratory Capability of Peyer’s Patch Germinal Center Cells

Peanut agglutinin (PNA) binds selectively to germinal center cells in mouse peripheral lymphoid organs. Using PNA as a marker, we have determined that Peyers patch germinal center cells are B cells with a unique phenotype---they express a low level of surface immunoglobulin (about 85% Ig+), predominantly of the IgA class (70% alpha+), with only 10% bearing surface IgM, and few if any expressing IgD. This phenotype identifies murine Peyers patch germinal center cells as fairly late cells in B cell differentiation, and suggests that they may be precursors of IgA-secreting plasma cells in the gut wall. In addition, we have described a means of purifying PNA+ Peyers patch lymphocytes, and have demonstrated that these cells lack functional receptors for high endothelial venules and fail to migrate to lymphoid organs in vivo. It is speculated that PNA may be a general marker for nonmigratory lymphocyte populations undergoing local differentiation.

Lymphocyte and Lymphoma Receptors Utilized in Differentiation, in Homing, and in Lymphomagenesis

The thymus is believed to be the major, if not the sole site of differentiation of T lymphocytes [1, 2]. During fetal development the thymus receives a bolus of precursors of T cells from the hematopoietic organs, probably the fetal liver and/or the yolk sac [3, 4]; these populations subsequently undergo self-renewal as well as maturation [5]. In adult life the thymus receives cells from the bone marrow at a very low level, but in times of stress, or after irradiation, there is a massive renewal of cells in the thymus from bone marrow precursors [2].