Significance of Toll-like Receptors Expression in Tumor Growth and Spreading: A Short Review

Toll-like receptors (TLRs) are considered now as crucial sensors of innate immunity. Their role in the recognition of pathogens and the initiation of adaptive immune responses against them is well known. However, in last years TLRs have been identified on several tumor cells, including human malignancies. Their expression in cancer was found to be twofold: either promoting or inhibiting tumor progression. It was also demonstrated that several TLRs agonists, either natural or synthetic ones, may have beneficial effect on tumor-mediated disease, leading to potentiation of immune response to tumor-associated antigens. TLR-agonist linked tumor immunotherapy is still in nascent state, but growing rapidly, also in the area of common human malignancies. To date, the most promising and the most frequently studied interaction in tumor immunotherapy trials seems to be TLR9 and its synthetic agonists

Phylotyping and Functional Analysis of Two Ancient Human Microbiomes

Background: The Human Microbiome Project (HMP) is one of the U.S. National Institutes of Health Roadmap for Medical Research. Primary interests of the HMP include the distinctiveness of different gut microbiomes, the factors influencing microbiome diversity, and the functional redundancies of the members of human microbiotas. In this present work, we contribute to these interests by characterizing two extinct human microbiotas. Methodology/Principal Findings: We examine two paleofecal samples originating from cave deposits in Durango Mexico and dating to approximately 1300 years ago. Contamination control is a serious issue in ancient DNA research; we use a novel approach to control contamination. After we determined that each sample originated from a different human, we generated 45 thousand shotgun DNA sequencing reads. The phylotyping and functional analysis of these reads reveals a signature consistent with the modern gut ecology. Interestingly, inter-individual variability for phenotypes but not functional pathways was observed. The two ancient samples have more similar functional profiles to each other than to a recently published profile for modern humans. This similarity could not be explained by a chance sampling of the databases. Conclusions/Significance: We conduct a phylotyping and functional analysis of ancient human microbiomes, while providing novel methods to control for DNA contamination and novel hypotheses about past microbiome biogeography. We postulate that natural selection has more of an influence on microbiome functional profiles than it does on the species represented in the microbial ecology. We propose that human microbiomes were more geographically structured during pre-Columbian times than today

Regulation of inhibitory and activating killer-cell Ig-like receptor expression occurs in T cells after termination of TCR rearrangements.

A small fraction of T cells expresses killer-cell Ig-like receptors (KIR), a family of MHC class I-specific receptors that can modulate TCR-dependent activation of effector functions. Although KIR(+) cells are enriched within Ag-experienced T cell subsets, the precise relationships between KIR(+) and KIR(-) T cells and the stage of KIR induction on these lymphocytes remain unclear. In this study, we compared KIR(-) and KIR(+) alphabeta T cell clones, sorted by means of the CD158b (KIR2DL2/KIR2DL3/KIR2DS2) specific mAb GL183. We isolated several pairs of CD158b(+) and CD158b(-) alphabeta T cell clones sharing identical productive and nonproductive TCR transcripts. We showed that expression of functional KIR on T cells is regulated after termination of TCR rearrangements. Transcriptional regulation of KIR genes was documented in multiple T cell clones generated from the same donor, and the presence of KIR transcripts was also detected in KIR(-) T cells. These results document a complex regulation of KIR expression in T cells at both pre and posttranscriptional levels, under the control of yet undefined signals provided in vivo

Human NK cell education by inhibitory receptors for MHC class I.

Natural killer (NK) cells recognize the absence of self MHC class I as a way to discriminate normal cells from cells in distress. In humans, this "missing self" recognition is ensured by inhibitory receptors such as KIR, which dampen NK cell activation upon interaction with their MHC class I ligands. We show here that NK cells lacking inhibitory KIR for self MHC class I molecules are present in human peripheral blood. These cells harbor a mature NK cell phenotype but are hyporesponsive to various stimuli, including MHC class I-deficient target cells. This response is in contrast to NK cells that express a single inhibitory KIR specific for self MHC class I, which are functionally competent when exposed to the same stimuli. These results show the involvement of KIR-MHC class I interactions in the calibration of NK cell effector capacities, suggesting its role in the subsequent "missing self" recognition