The progression of tuberculosis from a latent, sub-clinical infection to active disease that culminates in transmission of infectious bacilli is determined locally at the level of the granuloma. This progression takes place even in the face of a robust immune response that, while it contains infection, is unable to eliminate the bacterium. The factors or environmental conditions that influence this progression remain to be determined. Recent advances have indicated that pathogen-induced dysregulation of host lipid synthesis and sequestration plays a critical role in this transition. The foamy macrophage appears to be a key player in both sustaining persistent bacteria and contributing to the tissue pathology that leads to cavitation and release of infectious bacilli.
Although gammadelta T cells express clonally distributed T-cell receptors (TCRs), a hallmark of adaptive immunity, they are classically considered as innate-like effectors, owing to the high frequency of preactivated gammadelta T cells, with restricted antigen recognition repertoire in particular tissue locations. Actually, such features are shared only by a fraction of gammadelta T-cell subsets located in the skin and reproductive organ mucosa in rodents or in peripheral blood in humans. By contrast, other gammadelta subsets, e.g. those found in rodent and human spleen, show diverse antigenic reactivity patterns and mixed naive/memory phenotypes. Thus, gammadelta T cells are made of both 'primitive' subsets endowed with innate-like properties and 'evolved' subsets able to mount anamnestic responses like conventional major histocompatibility complex-restricted alphabeta T cells. In this article, we show that human gammadelta T cells, although heterogeneous, do share recurrent innate features that distinguish them from mainstream alphabeta T cells. In particular, most of them are activated on TCR- or natural killer receptor-mediated recognition of a restricted set of conserved yet poorly defined endogenous stress determinants. This rather simple recognition mechanism allows human gammadelta T cells to discriminate healthy cells from altered cells and to exert a variety of immunostimulatory or regulatory functions. The recent availability of synthetic gammadelta T-cell agonists mimicking these natural stress-induced ligands have fostered development of immunotherapeutic strategies, with broad indications against infectious and tumor diseases, which are briefly reviewed here.
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