Studies of lymphocyte dynamics in lymphopenic environments such as the neonatal mouse or in instances of cell transfer into genetically lymphopenic (Rag2-/-; CD3e-/-) recipients indicates that a striking proliferative response occurs on the part of some of the transferred cells and that such cells undergo 7 or more cell divisions within one week and display a memory phenotype at the end of this very striking response. In previous work, it was shown that the pretansfer of CD4 T cells into lymphopenic recipients would prevent newly introduced cells from undergoing rapid prolioferation. It was also shown that the capacity of the initially transferred cells to block proliferation by subsequently introduced cells correlated very strongly with the TCR repertoire complexity of the cells present as the time of the second transfer. Thus, although Rag2-/- mice that had received 30,000 or 2 million CD4 T cells had similar numbers of memory phenotype CD4 T cells 6 weeks after transfer, newly introduced cells showed striking proliferation in host that had previosuly received 30,000 cells but failed to proliferate in hosts that had previously received 2 million cells. The TCR complexity was far greater in the recipients of 2 million cells than in the recipients of 30,000 cells despite the similar numbers of cells present at equilibrium. Unit scientists observed that recipients of small numbers of CD4 T cells eventually developed a fulminant macrophage/ eosinophil pneumonia, characterized by the presence of alternatively activated macrophages, Ym1 crystals and eosinophils. These mice also showed an eosinophilic gastritis and a striking increase in the frequency of cells that produced IL-4, IL-13 and IL-5 in the lymph nodes. This syndrome bears a striking relationship to that observed in humans in which there is a limitation of thymic supply of T cells to the periphery, such as Omenn's syndrome, atypical complete DiGeorge syndrome and maternal engraftment in severe combined immunodeficency disease. If the transfers are carried out in mice that lack T cells but express B cells (CD3e-/- mice), profound induction of serrtum IgE is observed. It has now been shown that pretransfer of regulatory T cells will block the induction of the eosinophilic inflammatory disease induced by transfer of limited numbers of conventional CD4 T cells. However, this is observed only when the number of initally transferred regulatory T cells is relatively large (300,000); pre-transfer of 30,000 regulatory T cells does not block induction of disease even though the number of regulatory T cells at the time of the introduction of the convnetional T cells is the same (as a result of homeostatic expansion). This implies that regulatory T cells must have a suffiently complex TCR repertoire to allow them to block activation of conventional T cells and of disease induciton mediated by these cells.
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