IMMUNOBIOLOGY Brief report Immunomodulatory drug costimulates T cells via the B7-CD28 pathway

Although thalidomide (Thal) does not directly induce T-cell activation, it in-creases proliferation of T cells following CD3 activation. In this study, we exam-ined the immunomodulatory effects of a more potent analog of Thal, immuno-modulatory drug (IMiD), on T cells. Al-though IMiD3 does not directly stimu-late proliferation of normal donor CD3 T cells, it significantly costimulates pro-liferation of CD3 T cells induced by CD3 ligation (stimulation index [SI], 2.4), immature dendritic cells (DCs; SI, 2.1), and mature DCs (SI, 2.6). T-cell prolifera-tion triggered by DCs was abrogated by cytotoxic T lymphocyte antigen 4–immunoglobulin (CTLA-4–Ig), and IMiD3 partially overcomes this inhibi-tory effect. IMiD3 also overcomes the inhibitory effects of CTLA-4–Ig on Ep-stein-Barr virus (EBV) and influenza (Flu)–specific CD4 and CD8 T-cell re-sponses, as measured by cytokine cap-ture and enzyme-linked immunosorbent spot (ELISPOT) assay. IMiD3 did not induce up-regulation of CD28 expres-sion on T cells, or of CD80-CD86 expres-sion on dendritic cells. Importantly, IMiD3 triggers tyrosine phosphorylation of CD28 on T cells, followed by activa-tion of nuclear factor B (NF-B), a known downstream target of CD28 sig-naling. These results therefore define the costimulatory mechanism whereby IMiD3 induces T-cell activation and pro-vide the cellular and molecular basis for use of IMiD3 as an adjuvant in immuno-therapeutic treatment strategies for multiple myeloma. (Blood. 2004;103