The role of SOCS proteins in T cell function against infectious diseases

Among other genes of the JAK/STAT pathway, our group has been able to identify SOCS3 and CISH to be involved in the pathogenesis of human tuberculosis. Abrogation of SOCS expression and subsequent changes in cytokine signaling seem to affect crucial T cell responses and, therefore, the susceptibility to tuberculosis infection in patients.

Immune cells depend on extracellular signaling via cytokines. The JAK/STAT pathway is an important downstream signaling cascade activated by cytokine stimulation in immune cells and resulting in the activation of certain genes by STAT molecules, mediating the membrane-to-nucleus signaling. Among these genes are the so called SOCS genes (“suppressor of cytokine signaling”), which function as classical negative feedback inhibitors of STAT signaling.

SOCS regulate STAT signaling mainly by inhibition of STAT binding to the receptor, by targeting the receptor or JAK proteins for degradation, and by inhibition of JAK kinase activity.

A huge number of cytokines utilize the JAK/STAT pathway to mediate T cell maturation, differentiation, polarization and function in different types of T cells. As the JAK/STAT pathway only utilizes four JAKs (JAK1-3, TYK2) and seven STATs (STAT1-4, STAT5a, STAT5b, STAT6), which are feedback-regulated by eight SOCS (CISH, SOCS1-7), a certain specificity needs to be reached.

This specificity might be achieved by a certain lineage specificity, the duration and intensity of the cytokine signaling itself, protein half-life of STAT and SOCS proteins and the differential activation of several STATs by one cytokine, among others.

In autoimmunity and disease, this strictly regulated balance of JAK/STAT signaling can be disturbed, sometimes caused by genetic mutations or polymorphism in any step of the signaling pathway from the receptor itself to STAT-binding sites in target genes, leading to T cell dysfunction.

The JAK/STAT pathway is being investigated for more than twenty years now in concerns of allergy, autoimmunity, infectious diseases and oncogenesis. In comparison, the function of SOCS proteins is a relatively new topic to science and needs further investigation.

In order to further characterize the role of SOCS proteins in infectious diseases, we investigate the role of certain SOCS proteins in T cell differentiation and function by overexpression and/or knockdown assays via polychromatic lentiviral transduction in human primary T cells, with subsequent assessment of STAT and SOCS protein levels as well as cytokine profiles.

Researcher: Alptekin Güler