Paradoxical role of CD16+CCR2+CCR5+ monocytes in tuberculosis: efficient APC in pleural effusion but also mark disease severity in blood

Abstract

The role of CD16(-) and CD16(+) Mo subsets in human TB remains unknown. Our aim was to characterize Mo subsets from TB patients and to assess whether the inflammatory milieu from TB pleurisy modulate their phenotype and recruitment. We found an expansion of peripheral CD16(+) Mo that correlated with disease severity and with TNF-α plasma levels. Circulating Mo from TB patients are activated, showing a higher CD14, CD16, and CD11b expression and Mtb binding than HS. Both subsets coexpressed CCR2/CCR5, showing a potential ability to migrate to the inflammatory site. In tuberculous PF, the CD16(+) subset was the main Mo/MΦ population, accumulation that can be favored by the induction of CD16 expression in CD16(-) Mo triggered by soluble factors found in this inflammatory milieu. CD16(+) Mo in PF were characterized by a high density of receptors for Mtb recognition (DC-SIGN, MR, CD11b) and for lipid-antigens presentation (CD1b), allowing them to induce a successful, specific T cell proliferation response. Hence, in tuberculous PF, CD16(+) Mo constitute the main APC population; whereas in PB, their predominance is associated with the severity of pulmonary TB, suggesting a paradoxical role of the CD16(+) Mo subset that depends on the cellular localization.

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

“…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.…”

“…It is currently accepted that different Mo subsets may reflect developmental stages with distinct physiological functions [4] and that the CD16 + Mo subset constitutes a more mature form of the CD16 − subset [49]; thereby, the higher p38 activity in CD16 + Mos may contribute to their higher activation degree. In this regard, we suggest that CD16 + Mos are less prone to differentiate to DCs as a result of their more advanced commitment for a specific function compared with CD16 − Mos accordingly to their more activated phenotype [12].The differential capacity of Mo subsets to give rise to APCs populations has been reported in mice where two major populations have been identified on the basis of Ly6C and CX3CR1 expression [50]. In particular, it is known that in lungs DCs develop from both Ly6C high and Ly6C low Mos, while M s originate from Ly6C low Mos, which resemble the human CD16 + subset [41].…”

“…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 this study, we evaluated whether the imbalance in the relative proportion of the Mo subsets in TB patients could explain the altered differentiation toward DCs in terms of CD1 molecules and DC-SIGN expression. Our results show that altered CD1a − DC-SIGN low DCs are generated from CD16 + Mos, which are enriched in TB patients, involving a sustained p38 MAPK activity during their differentiation process.…”

“…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].…”

“…2013. 43: 335-347 an imbalance in the relative proportions of the subsets during acute inflammation [5] and several infectious diseases [6][7][8][9][10] including tuberculosis (TB) [11,12] has been described. TB, a disease that mainly affects the respiratory system, infects onethird of the world's population and kills 2 million people each year [13].…”