TRAF6 has a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Here we show that T cell-specific deletion of TRAF6 unexpectedly results in multiorgan inflammatory disease. TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway compared with wild-type T cells and, as a result, become resistant to suppression by CD4+ CD25+ regulatory T cells. These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell-intrinsic control mechanism to render responder T cells susceptible to tolerizing signals.

Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.

Th1-mediated cellular responses are important for protection in tuberculosis. However, the mechanisms and APC types responsible for initiating Th1 responses are not well understood. These studies show that macrophages and dendritic cells, albeit both being APC, respond differently following Mycobacterium tuberculosis infection and thereby have different consequences for the development of naive T cells. We report that M. tuberculosis-infected dendritic cells bias the polarization of OVA peptide-specific naive transgenic T cells to the Th1 phenotype, and, in contrast, in the presence of infected macrophages naive T cells do not develop a Th1 phenotype. Comparison of the cytokine profile expressed by the infected dendritic cells and macrophages revealed several differences, the most striking being that infected macrophages did not express the Th1-promoting cytokine IL-12. These studies also show that IL-10 is responsible for the failure of IL-12 production by M. tuberculosis-infected macrophages, and that the effects of IL-10 can be overcome by IFN-γ priming. We speculate that the observed difference in response of the two APC types to M. tuberculosis infection may be a reflection of their respective roles in immune initiation and granuloma regulation.