Monocyte differentiation towards a CD16+CD163+MerTK+CD206+pSTAT3+ phenotype plays a pathogenic role in severe tuberculosis

LASTRUCCI C; BÉNARD, A; BALBOA, L; PINGRIS, K; LENDOIRO, N; AL SAATI, T; POINCLOUX, R; KONDOVA, I; VERRECK, F; SASIAIN MC; NEYROLLES, O; MARIDONNEAU-PARINI, I; LUGO-VILLARINO, G; COUGOULE, C

Simposio; Host Response in Tuberculosis; 2015

Keystone Symposia on Molecular and Cellular Biology

The human monocyte compartment is composed by two major subsets based on CD16 expression. While CD16- monocytes predominate in the circulation of healthy individuals, we previously reported that there is an expansion of the CD16+ subset in TB patients. Whether CD16+ monocytes play a protective or pathogenic role in TB is unknown. Here, we show that the in vitro differentiation of CD16+ monocytes is dependent on STAT3 activation by IL-10 (derived from infected macrophages) in order to acquire a marker signature (CD163+MerTK+CD206+) and functional phenotype associated with an anti-inflammatory (M2) macrophage program, such as motile, immunosuppressive and poorly microbicidal properties. Strikingly, not only peripheral monocytes from TB patients exhibit a higher level of pSTAT3 and immunosuppressive properties, but also we detect increasing serum levels of soluble CD163 and MerTK according to disease severity. Moreover, there is a high incidence of CD16+CD163+MerTK+CD206+ monocytes within the pleural cavity of TB patients, alluding to a preferential recruitment of this cell phenotype to infectious sites. Consistent with these findings, treatment of monocytes from healthy individuals with pleural effusion fluid from TB patients activates STAT3 and enhances their migratory properties. Finally, we correlate the abundance of CD16+CD163+MerTK+CD206+pSTAT3+ cells with disease severity in the granuloma of M. tuberculosis-infected macaques. Collectively, this study argues for the pathogenic role of CD16+CD163+MerTK+CD206+pSTAT3+ monocytes and their potential as a target for TB therapy, and proposes the soluble detection of CD163 and MerTK as a diagnostic tool for disease severity.