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.