Upon first antigen encounter, naive CD8(+) T cells get activated, clonally expand, and can develop into very distinct subsets, such as short-living effector cells or different memory subpopulations. The origin of subset diversification is currently unknown, but qualitative and quantitative differences in early signals received by individual precursor cells have been suggested as a major determinant. We show that transfer of a single antigen-specific naive T cell into a normal recipient mouse allowed recovery of clonally expanded daughter cells upon immunization. With this experimental approach, we conclusively demonstrated that a wide range of diversity could develop out of a single precursor cell, including different types of effector and memory T cells. Interestingly, single-cell-derived subset diversification resembled that of polyclonal T cell responses in the same individual mouse, although differentiation patterns differed between immunization strategies. These data implicate that subset diversification is both shaped and synchronized during the expansion phase.

Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world’s population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1β production have been associated with increased risk for gastric cancer. To be active, pro–IL-1β must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow–derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1β upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori–induced IL-1β secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain–containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain–containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.

Key Points• Lowest numbers of ex vivo-selected CD8 1 memory T cells can reconstitute pathogen-specific immunity in immunocompromised hosts.Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) are threatened by potentially lethal viral manifestations like cytomegalovirus (CMV) reactivation. Because the success of today's virostatic treatment is limited by side effects and resistance development, adoptive transfer of virus-specific memory T cells derived from the stem cell donor has been proposed as an alternative therapeutic strategy. In this context, dose minimization of adoptively transferred T cells might be warranted for the avoidance of graft-versus-host disease (GVHD), in particular in prophylactic settings after T-cell-depleting allo-HSCT protocols. To establish a lower limit for successful adoptive T-cell therapy, we conducted low-dose CD8 1 T-cell transfers in the well-established murine Listeria monocytogenes (L.m.) infection model. Major histocompatibility complex-Streptamer-enriched antigen-specific CD62L hi but not CD62L lo CD8 1 memory T cells proliferated, differentiated, and protected against L.m. infections after prophylactic application. Even progenies derived from a single CD62L hi L.m.-specific CD8 1 T cell could be protective against bacterial challenge. In analogy, low-dose transfers of Streptamerenriched human CMV-specific CD8 1 T cells into allo-HSCT recipients led to strong pathogen-specific T-cell expansion in a compassionate-use setting. In summary, low-dose adoptive T-cell transfer (ACT) could be a promising strategy, particularly for prophylactic treatment of infectious complications after allo-HSCT. (Blood. 2014;124(4):628-637)

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