Stephen Manning

The CD28-Related Molecule ICOS Is Required for Effective T Cell-Dependent Immune Responses

While CD28 is critical for expansion of naive T cells, recent evidence suggests that the activation of effector T cells is largely independent of CD28/B7. We suggest that ICOS, the third member of the CD28/CTLA-4 family, plays an important role in production of IL-2, IL-4, IL-5, and IFNgamma from recently activated T cells and contributes to T cell-dependent B help in vivo. Inhibition of ICOS attenuates lung mucosal inflammation induced by Th2 but not Th1 effector populations. Our data indicate a critical function for the third member of the CD28 family in T cell-dependent immune responses.

Expression of the SH2D1A gene is regulated by a combination of transcriptional and post-transcriptional mechanisms

The SH2D1A gene, which is altered or deleted in patients with X‐linked lymphoproliferative disease, encodes the small protein SAP (for SLAM‐associated protein) that is expressed in T and NK cells. A 22‐bp fragment in close proximity to an initiator‐like site was defined as the basal promoter of mouse SH2D1A, and a highly homologous 33‐bp segment was defined as the human basal promoter. When an Ets consensus site was mutated, no reporter activity was detectable. Gel mobility supershift assays revealed that the two transcription factors Ets‐1 and Ets‐2 bind to the human and mouse sequences. The involvement of Ets‐1 and Ets‐2 in expression of SH2D1A was functionally confirmed by overexpression studies of their dominant‐negative forms. We also found that SH2D1A mRNA decays very rapidly in mouse T cells, and its 3′ untranslated region (UTR) has RNA‐destabilizing activity in transfection studies with reporter/3′ UTR constructs. As judged by RNA‐gel mobility shift assays, this rapid degradation of SH2D1A mRNA was due to a balance in binding of the factors AUF1 and HuR to its 3′ UTR. Although the SH2D1A mRNA level decreased upon triggering of the T cell receptor (TCR), the RNA degradation rate itself was not altered by TCR engagement.