Human T-cell development in SCID-hu mice: staphylococcal enterotoxins induce specific clonal deletions, proliferation, and anergy.
SCID-hu mice provide an in vivo model for studying the events of normal intrathymic human T-cell development and differentiation. We injected SCID-hu mice with staphylococcal enterotoxins (SE) and determined their effects on the development and responsiveness of human T-cell populations defined by their expression of CD4 and CD8, and the type of V beta molecule in their T-cell receptors. After single intraperitoneal injections of SEB or SEE, we observed specific effects on thymic T cells expressing a cognate V beta T-cell receptor (TCR) (V beta 12.1 in the case of SEB-treated SCID-hu mice and V beta 8.1 in the case of SEE-treated mice) using both immunohistochemical staining of thymic frozen sections and flow cytometric analyses. An injection of SEB resulted in a 32% decrease in the total percentages of V beta 12.1+ cells in thymic sections after 2 days, with the greatest effect seen in the medulla, without a demonstrable effect on V beta 5.2/5.3+ or V beta 8.1+ cells. Fluorescence-activated cell sorter analysis demonstrated that TCRhi thymocytes expressing a cognate V beta TCR declined transiently by 35% to 45% 1 to 2 days after the injection of SE. Analysis of thymic subpopulations showed decreases in the TCRhi CD4+8- and CD4-8+ cells and an increase in TCRlo CD4-8+ cells. Multiple injections of SE resulted in 50% to 60% decreases in cognate V beta TCR+ CD4+8- populations. Thymocytes prepared from SE-treated SCID-hu mice demonstrated specific anergy to the SE to which they had previously been exposed in vivo, but had a normal proliferative response to other superantigens in an in vitro assay. In contrast to the effects on thymic T cells, single injections of SE resulted in a twofold increase in the total numbers of circulating CD4+8- and CD4-8+ human T cells and a fourfold to eightfold increase in T cells expressing a cognate V beta TCR. Using SE as superantigens in SCID-hu mice, we have been able to induce antigen-specific clonal deletions, anergy, and proliferation of human T cells.
Waller
E K
EK
Division of Oncology, Stanford University Medical Center, CA 94305-5468.
Sen-Majumdar
A
A
Kamel
O W
OW
Hansteen
G A
GA
Schick
M R
MR
Weissman
I L
IL
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D004768:Enterotoxins / Q000494:pharmacology*; D006801:Humans; D016031:Liver Transplantation; D008213:Lymphocyte Activation / Q000187:drug effects*; D008212:Lymphocyte Depletion; D051379:Mice; D016513:Mice, SCID; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D013211:Staphylococcus aureus; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D013950:Thymus Gland / Q000637:transplantation; D014183:Transplantation, Heterologous
D015704:CD4 Antigens; D016827:CD8 Antigens; D004768:Enterotoxins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C049463:enterotoxin E, Staphylococcal; C031818:enterotoxin B, staphylococcal