Critical and Independent Role for SOCS3 in Either Myeloid or T Cells in Resistance to <i>Mycobacterium tuberculosis</i>

<div><p>Suppressor of cytokine signalling 3 (SOCS3) negatively regulates STAT3 activation in response to several cytokines such as those in the gp130-containing IL-6 receptor family. Thus, SOCS3 may play a major role in immune responses to pathogens. In the present study, the role of SOCS3 in <i>M. tuberculosis</i> infection was examined. All <i>Socs3^fl/fl LysM cre, Socs3^fl/fl lck cre</i> (with SOCS3-deficient myeloid and lymphoid cells, respectively) and <i>gp130^F/F mice</i>, with a mutation in gp130 that impedes binding to SOCS3, showed increased susceptibility to infection with <i>M. tuberculosis</i>. SOCS3 binding to gp130 in myeloid cells conveyed resistance to <i>M. tuberculosis</i> infection via the regulation of IL-6/STAT3 signalling. SOCS3 was redundant for mycobacterial control by macrophages <i>in vitro</i>. Instead, SOCS3 expression in infected macrophages and DCs prevented the IL-6-mediated inhibition of TNF and IL-12 secretion and contributed to a timely CD4+ cell-dependent IFN-γ expression <i>in vivo</i>. In T cells, SOCS3 expression was essential for a gp130-independent control of infection with <i>M. tuberculosis</i>, but was neither required for the control of infection with attenuated <i>M. bovis</i> BCG nor for <i>M. tuberculosis</i> in BCG-vaccinated mice. <i>Socs3^fl/fl lck cre</i> mice showed an increased frequency of γδ+ T cells in different organs and an enhanced secretion of IL-17 by γδ+ T cells in response to infection. <i>Socs3^fl/fl lck cre</i> γδ+ T cells impaired the control of infection with <i>M. tuberculosis</i>. Thus, SOCS3 expression in either lymphoid or myeloid cells is essential for resistance against <i>M. tuberculosis</i> via discrete mechanisms.</p></div