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

et al. (2013) Critical and Independent Role for SOCS3 in Either Myeloid or T Cells in Resistance to Mycobacterium tuberculosis. PLoS Pathog 9(7): e1003442. doi:10.1371/journal.ppat.1003442 Critical and Independent Role for SOCS3 in Either Myeloid or T Cells in Resistance to Mycobacterium tuberculosis Berit Carow 0 Ann-Kathrin Reuschl 0 Dolores Gavier-Wide n 0 Brendan J. Jenkins 0 Matthias Ernst 0 Akihiko Yoshimura 0 Benedict J. Chambers 0 Martin E. Rottenberg 0 David M. Lewinsohn, Portland VA Medical Center/Oregon Health and Science University, United States of America 0 1 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden, 2 Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences and National Veterinary Institute, Uppsala, Sweden, 3 Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University , Melbourne, Victoria , Australia , 4 Cell Signaling and Cell Death Division, Walter and Eliza Hall Institute of Medical Research , Melbourne, Victoria , Australia , 5 Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan, 6 Center of Infectious Medicine, Karolinska Institutet , Stockholm , Sweden 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 M. tuberculosis infection was examined. All Socs3fl/fl LysM cre, Socs3fl/fl lck cre (with SOCS3-deficient myeloid and lymphoid cells, respectively) and gp130F/F mice, with a mutation in gp130 that impedes binding to SOCS3, showed increased susceptibility to infection with M. tuberculosis. SOCS3 binding to gp130 in myeloid cells conveyed resistance to M. tuberculosis infection via the regulation of IL-6/STAT3 signalling. SOCS3 was redundant for mycobacterial control by macrophages in vitro. 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-c expression in vivo. In T cells, SOCS3 expression was essential for a gp130-independent control of infection with M. tuberculosis, but was neither required for the control of infection with attenuated M. bovis BCG nor for M. tuberculosis in BCG-vaccinated mice. Socs3fl/fl lck cre mice showed an increased frequency of cd+ T cells in different organs and an enhanced secretion of IL-17 by cd+ T cells in response to infection. Socs3fl/fl lck cre cd+ T cells impaired the control of infection with M. tuberculosis. Thus, SOCS3 expression in either lymphoid or myeloid cells is essential for resistance against M. tuberculosis via discrete mechanisms. - Funding: BJJ is supported by a Senior Medical Research Fellowship awarded by the Sylvia and Charles Viertel Foundation. This work was supported by the European Community 200732 HOMITB grant, the Karolinska Institutet, the Swedish Lung and Heart Foundation and the Swedish Research Council, as well as the Operational Infrastructure Support Program by the Victorian Government of Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, remains a leading public health problem worldwide. The global incidence of TB is rising with 8.8 million new cases and 2 million deaths each year [1]. However, while immune responses to TB clearly show their importance in host defence, it is clear that there are still gaps in our knowledge of the host factors determining the outcome of infection. Host responses of mycobacterial infections are primarily Th1 immune responses involving cellular effector mechanisms such as macrophage activation. IFN-c is known to be an important mediator of mycobacterial control during clinical and experimental infections [2]. IL-12 is crucial for optimal differentiation and maintenance of IFN-c-secreting antigen-specific Th1 cells [3,4], and in controlling mycobacterial infections in mice and man [5,6]. The suppressor of cytokine signalling (SOCS) proteins are a family of eight members that inhibit STAT activation by different receptors. SOCS proteins bind either the Janus-activated kinases (JAKs) directly inhibiting their kinase activity, or the intracellular domain of cytokine receptors thereby targeting the receptor complex for ubiquitination and subsequent proteasome-mediated degradation [7]. SOCS3 inhibits STAT3-mediated signalling by binding to the IL-6 receptor family subunit gp130, G-CSF, leptin and the IL-12 receptor [8]. Since SOCS3-deficient mice die during embryogenesis [9,10], the role of SOCS3 in vivo has been studied using conditional knockdown mice. Conditional knockdown of SOCS3 in macrophages protects mice from LPS shock by reducing the secretion of IL-12 and TNF due to the enhanced anti-inflammatory effect of STAT3 [11]. However, mice with SOCS3-deficient macrophages and neutrophils succumb to toxoplasmosis, probably due to reduced IL-12 and IFN-c responses [12]. Furthermore, SOCS3 can also inhibit STAT1 activation thereby preventing IFN-c-like responses in cells stimulated with IL-6 [13,14]. SOCS3 also may have several roles in T cell function. SOCS3 expression in T cells can both obstruct Tuberculosis is a severe disease caused by infection with the intracellular bacteria Mycobacterium tuberculosis. The protein suppressor of cytokine signalling 3 (SOCS3) inhibits the responses of cells to several cytokines and growth factors that signal via the STAT3 transcription factor. Since STAT3 is a major controller of immune and inflammatory responses, we studied the role of SOCS3 in the control of infection with M. tuberculosis. Mice deficient in the expression of SOCS3 either in myeloid or lymphoid cells were extremely susceptible to infection with M. tuberculosis as measured by elevated bacterial levels, worsened pathology and reduced survival. In myeloid cells, SOCS3 hindered a detrimental role of IL-6. In absence of SOCS3, IL-6 hampered the release of IL-12 by antigenpresenting cells. In T cells, SOCS3-mediated protection was independent of IL-6 signals, and of adequate IFN-c secretion by antigen-specific T cells. Instead, SOCS3 inhibited the in vivo accumulation of, and the IL-17 secretion by cd+ T cells. cd+ T cells accounted in part for the susceptibility to M. tuberculosis infection of mice with SOCS3-deficient T cells. Thus, SOCS3 controls diverse immune mechanisms of myeloid and lymphoid cells that are required for containment of M. tuberculosis. the differentiation of inflammatory IL-17-producing Th17 cells [15,16] and inhibit the secretion of anti-inflam (...truncated)