The present study shows that tetanus toxoid (tet) booster releases to the human circulation 2 subsets of specific plasma cells (PCs), as defined by phenotype and morphology, which clearly differed in the staining capacity of their cytoplasmic antibodies (Abs) with fluorescein isothiocyanate (FITC)-labeled tet-fragment C (tetC). These cells, called tetC HIGH
IntroductionPlasma cells (PCs) represent the final and effector phase of the B lymphocyte differentiation process. There is accumulating evidence to support the view that in mammals, the PC compartment comprises a biologically complex variety of cell stages. In systemic humoral responses, specific PCs initially appear in antigen (Ag)-induced extrafollicular foci of secondary lymphoid tissues. In the presence of sufficient Ag, PCs are subsequently generated in the follicular germinal centers. [1][2][3][4][5] Most of the early-generated PCs die within a few days by apoptosis. [5][6][7] Later, some of the recently generated PCs migrate through the circulation and home into specialized survival niches present mainly in the bone marrow (BM) 5,[8][9][10][11][12][13][14][15] and, less commonly, in the spleen and probably in other lymphoid organs, [16][17][18] as well as in inflamed tissues. 19 In these locations, PCs are thought to produce antibodies (Abs) for prolonged periods of time. Thus, it is well established that the BM PC pool is responsible for the generation of long-lasting serum Ab levels. 5,[9][10][11][12]20 The mechanisms involved in the arrival and retention of PCs into the BM niches are beginning to be known. In this respect, the interaction between the chemokine receptor CXCR4 expressed on PCs and its ligand CXCL12 is required for the establishment of the BM PC compartment in mice, 21 and probably in humans. [22][23][24] Although the auxiliary cellular components of the BM PC niches still remain poorly defined, [13][14][15]25 they are believed to convey the necessary signals to support the prolonged survival of immigrant PCs. Some of the molecular mechanisms that participate in this process have been identified, including IL-6, APRIL, and certain ligands of PC adhesion molecules. [13][14][15]25,26 In spite of these findings, it remains uncertain whether occupancy of BM PC niches is merely a random phenomenon, or whether intrinsic factors of PCs are involved in the generation of the BM PC compartment.It is now clear that, a few days after booster immunization, Ag-specific PCs are transiently observed in the blood, and this circulating PC subset appears to contain the precursors of BM PCs. 27,28 In humans, a conventional booster immunization with tetanus-toxoid (tet) induces the temporary appearance in the blood of tet-specific PCs. 23,24,[29][30][31] These tet-specific circulating PCs exhibit features of intermediate maturity between early PCs and PCs present in deposit organs such as the BM, 23,28,31 and the occurrence of these PCs is temporarily and functionally associated with the high-rate phase of serum anti-tet Ab formation and, accordingly, ...