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"Drawn from authors' own data plus published data from other groups. In published data, there is considerable variation due to age, breed differences and exposure to pathogens. "Parentheses refer to previous designation. NAc, data not available.

molecules, or express only one. These phenotypic differences either identify functionally distinct dendritic cell subsets or represent different stages of differentiation of the one dendritic cell lineage. Dendritic-cells in afferent lymph are functionally significant antigen-presenting cells involved in carriage of antigen in an immunogenic form from the skin to the draining node. Dendritic cells have a high level of IgM and IgGl 'cytophilic' immunoglobulin. This passively acquired immunoglobulin may be physiologically important in antigen processing, as it allows dendritic cells to specifically concentrate foreign antigen and localize it in the form of immunogenic complexes for internalization and presentation to T cells. Despite a high afferent input of dendritic cells into the node few, if any, appear in the efferent lymph, suggesting that in sheep there is a high turnover of dendritic cells within the node. This is consistent with studies in other species that show that dcndritic cells in afferent lymph are the precursors of the T antigen-presenting cells of the paracortical region of the lymph node which have a rapid turnover.

Emigration of T cells from the skin to afferent lymph across the peripheral vascular endothelium is profoundly influenced by the cytokines IEN-y and TNF, Intradermal injection of each cytokine can induce significant lymphocyte migration across the vascular endothelium into afferent lymph. It is likely that these cytokines play an important role in the emigration of recirculating lymphocytes at the site of immune or inflammatory responses in the skin. The evaluation of the in vivo activities of cytokines is another good example of how the lymphatic can-nulation model can be used to investigate cytokine physiology.

Lymph node

A total of 90% of lymphocytes within a lymph node are derived from the blood; the remainder come from lymphoproliferation within the node and afferent lymph. The route of entry is across a specialized part of the vascular endothelium known in other species as the high endothelial venule (HEV). There is no morphological equivalent structure in sheep, but functionally the postcapillary venules are the same as in rodents and humans. Lymphocyte-HEV interaction is now known to involve a complex family of adhesion molecules including homing receptors (or selectins) on lymphocytes and complementary ligands on endothelial (addressins) and cell matrix proteins. The nonrandom patterns of lymphocyte recirculation through different immunological compartments have been well defined in the sheep. Blast cells from intestinal lymph home to the lamina propria of gut, whereas blast cells from peripheral nodes home to spleen and lymph nodes. Within the small lymphocyte recirculating pool, there are subsets of lymphocytes that preferentially recirculate through the skin, peripheral nodes, or mucosal-associated lymphoid tissue such as the Peyer's patch and mesenteric node. These studies give physiological credence to more recent in vitro studies on lymphocyte-HEV which have clearly established the differential selectivity for lymphocyte subset adhesion to specialized vascular endothelial cells in peripheral or mucosal-associated tissues. CD4+ T cells are selectively enriched over CD8+ T cells in lymph nodes and B cells show a preferential traffic through gut-associated lymphoid tissue. Vascular endothelial cells in antigen-stimulated nodes in the sheep express MHC class II and can act as antigen-presenting cells to recruit selectively antigen-specific T cells into the node. In antigen-stimulated nodes, the rate of entry of lymphocytes is 2-4 x 104 cells s"1. The immediate response to antigen challenge is a phenomenon known as cell shutdown, wherein the output during the first 24 h in response to secondary challenge with antigen is reduced by 90%. During this time, there is an increased input of cells into the node. This is followed 24-28 h later by a 5- to 6-fold increase in lymphocyte output in efferent lymph. These changes in cell kinetics reflect vascular changes within the node and inhibition of intranodal traffic by prostaglandins.

Efferent lymph

Immunological memory is disseminated from the node via the efferent lymph. Studies by Hall and Morris established that if all the cells leaving an antigen-stimulated lymph node were removed from the sheep via the cannulated lymphatic, then no priming for a secondary response occurred. If the efferent lymph cells were returned intravenously, then immunological memory was established. Exit of T cell subsets from the node following antigen stimulation is nonrandom. Studies of secondary challenge with antigens show that there is a biphasic exit of CD4+ T cells followed by CD8+ T cells, presumably reflecting the sequential activation of CD4 and CD 8 within the node. Efferent T cells contain a higher proportion of ot(3 TCR+ T cells than yƓ and contain cells of both memory and naive phenotype. Efferent lymph T cells draining viral infected lymph nodes contain precursor cytotoxic T lymphocytes (CTLs) and the time course and kinetics of the CTL response to viral infection has shown that pCTLs can be detected as early as 5-7 days after infection.

This brief review of the ovine systems has outlined some of the more intriguing aspects of lymphocyte biology. The availability of cellular and molecular markers for the ovine immune system has confirmed the immense value of the sheep to fundamental immunology and provides for the future a central focus for the essential integration of the in vitro immune system(s) into a physiological framework.

See also: Adhesion molecules; High endothelial venules; Immune system, anatomy of; Lymphatic system; Lymph nodes; Lymphocyte trafficking; Lymphocytes; Maturation of immune responses; Ungulate immune systems.

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