Epidemiological studies regarding many successful vaccines suggest that vaccination may lead to a reduction in child mortality and morbidity worldwide, on a grander scale than is attributable to protection against the specific target diseases of these vaccines. These non-specific effects (NSEs) of the Bacille Calmette-Guérin (BCG) vaccine, for instance, implicate adaptive and innate immune mechanisms, with recent evidence suggesting that trained immunity might be a key instrument at play. Collectively referring to the memory-like characteristics of innate immune cells, trained immunity stems from epigenetic reprogramming that these innate immune cells undergo following exposure to a primary stimulus like BCG. The epigenetic changes subsequently regulate cytokine production and cell metabolism and in turn, epigenetic changes are regulated by these effects. Novel -omics technologies, combined with in vitro models for trained immunity and other immunological techniques, identify the biological pathways within innate cells that enable training by BCG. Future research should aim to identify biomarkers for vaccine heterologous effects, such that they can be applied to epidemiological studies. Linking biological mechanisms to the reduction in all-cause mortality observed in epidemiological studies will strengthen the evidence in favor of vaccine NSEs. The universal acceptance of these NSEs would demand a re-evaluation of current vaccination policies, such as the childhood vaccination recommendations by the World Health Organization, in order to produce the maximum impact on childhood mortality.

Toll-like receptors (TLRs) constitute a family of nonpolymorphic receptors that are devoted to pathogen recognition. In this work, we have explored the impact of TLR ligands (TLR-L) on human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). We show that HSCs and HPCs have a comparable pattern of expression of TLR transcripts characterized by the predominance of TLR1, -2, -3, -4 and -6. In longterm cultures of HSCs, HPCs and stromal cells, most TLR-L profoundly inhibited B-cell development while preserving or enhancing the production of myeloid cells. In short-term cultures, the TLR1/2 ligand PAM 3 CSK 4 induced a large proportion of HPCs to express markers of the myelomonocytic lineage. PAM 3 CSK 4 induced only marginal expression of myeloid lineage markers on HSCs but promoted their myeloid commitment as revealed by their acquisition of the phenotype of multi-and bipotential myeloid progenitors and by upregulation of the transcription factors PU.1, C/EBPa and GATA-1. Our results suggest that TLR agonists can bias the lineage commitment of human HSCs and shift the differentiation of lineage-committed progenitors to favor myelopoiesis at the expense of lymphoid B-cell development.

Plasma cells (PC) are the effector cells of the humoral Ab response. Unlike other dedicated secretory cells, they exist as two populations with opposite cell fates: short-lived and long-lived PC. Upon transformation they lead to an incurable neoplasia called multiple myeloma. In this study we have explored the molecular mechanism of PC death. Our data show that their apoptotic pathway is unique among other hemopoietic cells inasmuch as neither the death receptors nor the mitochondria play the central role. PC apoptosis is initiated by activation of Bax at the endoplasmic reticulum membrane and subsequent activation of the endoplasmic reticulum-associated caspase-4 before the release of mitochondrial apoptogenic factors. Together, our observations indicate that the cardinal function of PC (i.e., Ig secretion) is also the cause of their death.