W M Gallatin

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.

Homing receptors and metastasis.

As discussed in the preceding sections, there are several indications that the lymphocyte homing receptors involved in the normal process of lymphocyte recirculation are also relevant to the behavior of metastatic cells. Cell fusion experiments indicate that previously nonmetastatic cells can acquire metastatic capacity from fusion with normal lymphocytes. Murine T lymphomas that bear high levels of functional homing receptors can metastasize to peripheral lymphoid organs, whereas those lymphomas lacking homing receptors cannot. Virtually all lymph node metastases of lymphomas contain a high proportion of MEL-14hi cells, even if the primary tumor has been selected to be relatively deficient in these cells. Further investigations of the biology of lymphocyte homing receptors will reveal whether or not there are additional lymphocyte homing receptors and will clarify the role of lymphocyte homing receptors in metastasis. Antibodies against three lymphocyte homing receptors could therefore be useful for diagnosis and treatment of metastatic disease.

T cell clones: a model of a non-recirculating phase of T cell differentiation.

Cloned lines of T lymphocytes have been valuable in investigating many of the in vitro properties of thymus-derived lymphocytes. When such clones have been tested in vivo, however, they have generally shown much less activity than they have in vitro. Thus, cytolytic T cell (Tc) clones that are highly active in lysing tumor target cells in vitro are poorly effective in causing rejection of the same cells in vivo, unless they are injected into the same site as the tumor cells1,2. Similarly, in vitro T cell clones efficiently mediate delayed hypersensitivity only when injected at the same site as the relevant antigen3.

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].