title: Suppressors of cytokine signaling inhibit effector T cell responses during Mycobacterium tuberculosis infection.
abstract: Protective immune responses during Mycobacterium tuberculosis (M. tuberculosis) infection are regulated at multiple levels and critically dependent on the balance in the secretion of pro-inflammatory and regulatory cytokines. A key factor that governs this balance at the cellular level is suppressors of cytokine signaling (SOCS). We recently demonstrated that toll-like receptor 2 and dendritic cell (DC)-SIGNR1 differentially regulate SOCS1 expression in DCs during M. tuberculosis infection. This consecutively regulated IL-12 production and determined M. tuberculosis survival. In this study, we characterized the role of SOCS1 in regulating effector responses from CD4(+) and CD8(+) T cells during M. tuberculosis infection. Our data indicate that T cells from M. tuberculosis-infected mice show increased and differential association of SOCS1 with CD3 and CD28, when compared with uninfected mice. While SOCS1 displays increased association with CD3 than CD28 in CD4(+) T cells; SOCS1 is associated more with CD28 than CD3 in CD8(+) T cells. Further, SOCS1 shows increased association with IL-12 and IL-2 receptors in both CD4(+) and CD8(+) T cells from infected mice when compared with naive mice. Silencing SOCS1 in T cells increased signal transduction from T cell receptor (TCR) and CD28 with enhanced activation of key signaling molecules and proliferation. Significantly, SOCS1-silenced T cells mediated enhanced clearance of M. tuberculosis inside macrophages. Finally, adoptive transfer of SOCS1-silenced T cells in M. tuberculosis-infected mice mediated significant reduction in M. tuberculosis loads in spleen. These results exemplify the negative role played by SOCS1 during T cell priming and effector functions during M. tuberculosis infection.
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi, India. 2004.varsha@gmail.com
authors.forename: Varsha
authors.initials: V
authors.lastname: Srivastava
authors.forename: Mohit
authors.initials: M
authors.lastname: Vashishta
authors.forename: Shashank
authors.initials: S
authors.lastname: Gupta
authors.forename: Rupak
authors.initials: R
authors.lastname: Singla
authors.forename: Neeta
authors.initials: N
authors.lastname: Singla
authors.forename: Dighamber
authors.initials: D
authors.lastname: Behera
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000032:analysis; D017252:CD3 Complex / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D014376:Tuberculosis / Q000276:immunology* / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; D015815:Cell Adhesion Molecules; D016207:Cytokines; D018664:Interleukin-12; D007376:Interleukin-2; D037181:Lectins, C-Type; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D053707:Receptors, Interleukin-12; D015375:Receptors, Interleukin-2; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051195:Toll-Like Receptor 2; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C491590:Socs1 protein, mouse; C493486:Tlr2 protein, mouse