Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selectin on T cells during the virgin to memory cell transition.
Conventional virgin lymphocytes of a given class show relatively homogeneous recirculation through secondary lymphoid tissues, whereas memory/effector populations are composed of distinct subsets with differential, often tissue-selective migratory capability. In keeping with these observations, CD45RAhigh/ROlow "virgin" T cells in human peripheral blood uniformly express the peripheral lymph node homing receptor (HR) L-selectin, whereas among the CD45RAlow/ROhigh "memory/effector" subset, the expression of this HR is bimodal. To investigate the mechanisms responsible for the generation of memory/effector T cell subsets with differential homing potential, we developed a multiparameter flow cytometric technique that defines a common pathway of post-thymic T cell differentiation in secondary lymphoid tissues. Our analyses indicate that the virgin to memory T cell transition is characterized by a stepwise, unidirectional progression through distinct CD45RA+/RO+ intermediates that allow the in vivo discrimination of early, middle, and late transitional T cells. In normal peripheral blood, few T cells with a transitional phenotype are identified, but in secondary lymphoid tissues, 2 to 10% of T cells have this phenotype, including those CD45RA+ T cells that 1) are morphologically blasts, 2) are in S or G2/M phase of the cell cycle, or 3) express activation Ag. General adhesion molecules (LFA-1, LFA-3, ICAM-1) are uniformly up-regulated concordant with changes in T cell expression of CD45RA/RO in all tissues examined. Early in the transition, L-selectin is also uniformly up-regulated, but in subsequent stages, T cell expression of this HR is preferentially down-regulated in mucosal lymphoid tissues, and retained in peripheral lymph node. Differential regulation of L-selectin can also be demonstrated in vitro by the activation of virgin T cells in the presence of specific cytokines--IL-2 induces L-selectin down-regulation, whereas IL-6 and particularly TGF-beta 1 promote L-selectin up-regulation. Taken together, these findings support the hypothesis that local microenvironments within particular secondary lymphoid tissues influence HR expression at the time of CD45RA/RO conversion, and thereby contribute to the formation of CD45RAlow/ROhigh memory/effector T cell populations with tissue-selective homing behavior.
Picker
L J
LJ
Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235-9072.
Treer
J R
JR
Ferguson-Darnell
B
B
Collins
P A
PA
Buck
D
D
Terstappen
L W
LW
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D018845:CD11 Antigens; D015815:Cell Adhesion Molecules / Q000032:analysis*; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D007156:Immunologic Memory; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D017493:Leukocyte Common Antigens / Q000032:analysis; D008198:Lymph Nodes; D016201:Receptors, Lymphocyte Homing / Q000032:analysis*; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D018845:CD11 Antigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D006684:HLA-DR Antigens; D016201:Receptors, Lymphocyte Homing; D018799:Intercellular Adhesion Molecule-1; D019041:L-Selectin; D017493:Leukocyte Common Antigens