Mycobacterium tuberculosis impairs dendritic cell response by altering CD1b, DC‐SIGN and MR profile

Abstract

During a chronic infection such as tuberculosis, the pool of tissue dendritic cells (DC) must be renewed by recruitment of both circulating DC progenitors and monocytes (Mo). However, the microenvironment of the inflammatory site affects Mo differentiation. As DC are critical for initiating a Mycobacterium tuberculosis-specific T-cell response, we argue that interference of M. tuberculosis with a correct DC generation would signify a mechanism of immune evasion. In this study, we showed that early interaction of c-irradiated M. tuberculosis with Mo subverts DC differentiation in vitro. We found that irradiated M. tuberculosis effect involves (1) the loss of a significant fraction of monocyte population and (2) an altered differentiation process of the surviving monocyte subpopulation. Moreover, in the absence of irradiated M. tuberculosis, DC consist in a major DC-specific intercellular adhesion molecule 3-grabbing non-integrin receptor (DC-SIGN high )/CD86 low and minor DC-SIGN low /CD86 high subpopulations, whereas in the presence of bacteria, there is an enrichment of DC-SIGN low /CD86 high population. Besides, this population enlarged by irradiated M. tuberculosis, which is characterized by a reduced CD1b expression, correlates with a reduced induction of specific T-lymphocyte proliferation. The loss of CD1molecules partially involves toll-like receptors (TLR-2)/p38 MAPK activation. Finally, several features of Mo, which have been differentiated into DC in the presence of irradiated M. tuberculosis, resemble the features of DC obtained from patients with active tuberculosis. In conclusion, we suggest that M. tuberculosis escapes from acquired immune response in tuberculosis may be caused by an altered differentiation into DC leading to a poor M. tuberculosis-specific T-cell response.

Impaired dendritic cell differentiation of CD16‐positive monocytes in tuberculosis: Role of p38 MAPK

“…2); thereby the numbers of DCs derived from both Mo subsets were adjusted for functional analysis. This higher tendency of the CD16 + Mo subset to cell death has also been observed when CD16 + Mos were differentiated into M s [45] supports our conclusion that CD16 + Mos have a more activated phenotype.The relevance of the lack of CD1 molecules displayed by DCs derived from CD16 + Mos was supported by the association between the lower CD1b expression on DCs with their declined ability to present Mtb Ags [21]. In this line, it has been demonstrated that CD1-restricted T cells are expanded in TST + HSs and that CD1-restricted T-cell responses are absent or drastically reduced in TB patients [46], indicating an helpful role of CD1 molecules during Mtb infection.…”

“…Interestingly, since IL-1β has been described as an IL-12-inducing agent on human , the reduction of IL-1β + cells observed in CD16 + Mo-DCs could be associated with the low levels of IL-12 + cells. As TB patients have a high percentage of circulating CD16 + Mos [11,12], this dichotomy in the differentiation fate of Mo subsets can explain the impairment observed in Mo-derived DCs from TB patients [21]. In addition, we observed that CD16 + depletion in Mos from TB patients improved the differentiation toward DCs and that the addition of CD16 + Mos impaired the differentiation of Mos from HSs.…”

“…Since peripheral Mos from TB patients displayed a shift toward the CD16 + Mo subset [12] and failed to differentiate into CD1a + DC-SIGN high DCs [21], we wondered if the imbalance of Mo subsets could be associated to the altered DC phenotype observed in TB patients. As it is shown in Figure 5A, the percentages of CD16 + Mos from TB patients correlated moderately with the percentages of the altered DC-SIGN low CD86 high DC population (p < 0.05, n = 25).…”

“…On one hand, Mtb has a high content of antigenic lipids, which can be presented to CD1-restricted lipid-specific T lymphocytes [24], and on the other hand, DC-SIGN has been described as the main Mtb receptor on human DCs [25]. We have previously demonstrated that Mos from healthy subjects (HSs) exposed to IL-4 and GM-CSF generate mainly CD1a + CD14 − DC-SIGN high CD86 low DCs, which are efficient APCs for Mtb-specific T cells, while Mos from TB patients fail to differentiate into DCs generating a CD1a − CD14 + DC-SIGN low CD86 high cell population [21], which induces a low specific T-cell proliferation in response to Mtb [26]. Moreover, it has been demonstrated that the circulating CD16 + Mo subset is increased in TB patients [11,12].…”

“…In fact, the remarkable developmental plasticity of Mos allows them to differentiate into diverse DC populations, and multiple local mediators resulting from inflammatory and infectious processes can modulate their differentiation [19]. Mtb has been extensively described to be able to impair Mo differentiation as an escape mechanism, contributing to mycobacterial intracellular persistence [20,21]. Indeed, it has been reported that Mtb is able to affect Mo differentiation in lung tissue [22], therefore the modulation of DC generation by Mtb may result in different physiopathological outcomes of the infection.…”