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

Abstract

Tuberculosis (TB) is one of the world's most pernicious diseases mainly due to immune evasion strategies displayed by its causative agent Mycobacterium tuberculosis (Mtb). Blood monocytes (Mos) represent an important source of DCs during chronic infections; consequently, the alteration of their differentiation constitutes an escape mechanism leading to mycobacterial persistence. We evaluated whether the CD16 + /CD16 − Mo ratio could be associated with the impaired Mo differentiation into DCs found in TB patients. The phenotype and ability to stimulate Mtb-specific memory clones DCs from isolated Mo subsets were assessed. We found that CD16 − Mos differentiated into CD1a + DC-SIGN high cells achieving an efficient recall response, while CD16 + Mos differentiated into a CD1a − DC-SIGN low population characterized by a poor mycobacterial Ag-presenting capacity. The high and sustained phosphorylated p38 expression observed in CD16 + Mos was involved in the altered DC profile given that its blockage restored DC phenotype and its activation impaired CD16 − Mo differentiation. Furthermore, depletion of CD16 + Mos indeed improved the differentiation of Mos from TB patients toward CD1a + DC-SIGN high DCs. Therefore, Mos from TB patients are less prone to differentiate into DCs due to their increased proportion of CD16 + Mos, suggesting that during Mtb infection Mo subsets may have different fates after entering the lungs. Keywords: Dendritic cells r Monocyte differentiation r Tuberculosis See accompanying Commentary by Lugo-Villarino and NeyrollesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMonocytes (Mos) are large circulating leukocytes of the myeloid lineage that mediate essential functions of innate immunity including phagocytosis and cytokine production [1,2]. Mos are produced Correspondence: Dr. Luciana Balboa e-mail: luciana_balboa@hotmail.com in the bone marrow and released into the blood, and circulate in blood or reside in a spleen reservoir and, upon tissue infiltration they can differentiate into macrophages (M s) or DCs. Although human blood Mos are a highly heterogeneous population, two main subsets have been described: CD14 + CD16 − "classical" Mos are the major Mo population and CD14 + CD16 + Mos, the minor one (5-10% of total Mos). The latter subset has a more mature phenotype and an enhanced proinflammatory activity [3]. This heterogeneity has led to the hypothesis that Mos are committed to specific functions prior to tissue infiltration [4]. Also, C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 336Luciana Balboa et al. Eur. J. Immunol. 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]. The success o...

Dendritic Cells Differentiated from Human Umbilical Cord Blood-Derived Monocytes Exhibit Tolerogenic Characteristics

“…For example, unlike our findings, some of previous studies have demonstrated that CD14 + CD16 + monocytes differentiate into CD1a -DCs exhibiting low immunostimulatory potencies, compared to CD1a + DCs differentiated from CD14 + CD16 -monocytes [18,19]. In addition, monocytes consisting of mostly CD14 + CD16 -cells could differentiate into CD1a -DCs upon exposure to inflammatory mediators such as microbial molecular patterns [34] and phospholipid metabolites including PGE2 [29,32].…”

“…Monocytes consist of two populations, CD14 + CD16 -classical monocytes and CD14 + CD16 + non-classical monocytes [17], which differentiate into distinct DC subsets [18,19]. The proportion of CD14 + CD16 + monocytes is significantly increased in the blood of patients with systemic inflammatory diseases such as bacterial sepsis [20].…”

Manipulation of the Mononuclear Phagocyte System by Mycobacterium tuberculosis

“…Together, the modulation of these factors may be responsible for a bystander effect that allows M. tuberculosis to subvert the differentiation of monocytes into dendritic cells that are deficient in priming naïve T cells and, instead, contribute to pathogenic dissemination (Mariotti et al 2002;Skold and Behar 2008;Rajashree et al 2009). This premise is in line with the imbalance in the relative proportions of blood-circulating monocytes observed in tuberculosis patients, in which the abundance of the CD14 þ CD16 þ subset is accentuated and shown to have a defective differentiation program toward functional dendritic cells (Vanham et al 1996;Balboa et al 2013). In the case of IL-10, it was shown to be part of the bystander effect induced by M. tuberculosis to inhibit the differentiation of human monocytes into CD1c þ DCs, suggesting it plays an important role in the recruitment of dendritic cell precursors that may be incapable to activate efficiently the adaptive immune response (Remoli et al 2011).…”

Tuberculosis is associated with expansion of a motile, permissive and immunomodulatory CD16+ monocyte population via the IL-10/STAT3 axis

“…This unbalance in the monocyte population is also associated with a higher cell-surface expression for CD14, CD11b, toll-like receptor-2 (TLR2), TLR5, chemokine C-C motif receptor-1 (CCR1), CCR2 and CCR5, as compared with that of healthy individuals [18]. Functional characterization in vitro shows that monocytes isolated from TB patients are refractory to efficient dendritic cell (DC) differentiation and deficient in the activation of T lymphocytes, as compared with monocytes from healthy donors [19,20]. The cause and consequence of this unbalance are still relatively unknown.…”