Unique cytokine production profile of anergic human T cells in SCID-hu mice after staphylococcal enterotoxin B administration

Severe combined immunodeficient mice transplanted with human organs (SCID- hu mice), provide a unique in vivo model for studying human intrathymic T cell selection and development of tolerance. In vivo administration of staphylococcal enterotoxin B (SEB) to SCID-hu mice causes intrathymic clonal deletion of SEB-specific Vβ⁺ T cells that occurs already at the immature CD4⁺ 8⁺ double positive stage. The expression of activation markers such as CD25, CD71, and HLA-DR was specifically increased on Vβ⁺ T cells responding to SEB. The remaining SEB-specific human T cells that had not been deleted in vivo failed to proliferate when rechallenged with SEB in vitro. These SEB- specific T cells that were rendered anergic in vivo had a unique cytokine production profile. They failed to produce IL-2, which correlated with the lack of proliferation of these cells. In addition, they failed to produce TNF-α. However, the anergized T cells synthesized considerable amounts of IFN-γ, granulocyte-macrophage CSF and IL-10 after SEB stimulation. This clonal anergy can be completely reversed in vitro by stimulating the SEB- specific cells in the presence of exogenous IL-2 or by triggering of the CD28/CTLA-4 activation pathway. Under these stimulation conditions, anergic T cells produced levels of IL-2 and TNF-α that were comparable to their non- anergized counterparts, whereas the levels of granulocyte-macrophage CSF, IL- 10 and IFN-γ, production were even higher. Collectively, these data demonstrate that in vivo administration of SEB to SCID-hu mice leads to activation, deletion, and anergy of SEB-specific human thymocytes and that the production of IL-2 and TNF-α is selectively switched off in these anergic T cells.