Interleukin 12 (IL-12) family cytokines: Role in immune pathogenesis and treatment of CNS autoimmune disease

Abstract

Cytokines play crucial roles in coordinating the activities of innate and adaptive immune systems. In response to pathogen recognition, innate immune cells secrete cytokines that inform the adaptive immune system about the nature of the pathogen and instruct naïve T cells to differentiate into the appropriate T cell subtypes required to clear the infection. These include Interleukins, Interferons and other immune-regulatory cytokines that exhibit remarkable functional redundancy and pleiotropic effects. The focus of this review, however, is on the enigmatic Interleukin 12 (IL-12) family of cytokines. This family of cytokines plays crucial roles in shaping immune responses during antigen presentation and influence cell-fate decisions of differentiating naïve T cells. They also play essential roles in regulating functions of a variety of effector cells, making IL-12 family cytokines important therapeutic targets or agents in a number of inflammatory diseases, such as the CNS autoimmune diseases, uveitis and multiple sclerosis.

Keywords: Adoptive B cell therapy; Autoimmune disease; Cytokine therapy; IL-12 family cytokines; Regulatory B cells (Bregs and i35-Bregs).

Figure 1

The IL-12 cytokine family and its heterodimeric receptors. The family is comprised of four heterodimeric cytokines that share receptor components and activate the overlapped JAK/STAT pathways. Each IL-12 family cytokines is comprised of a helical alpha subunit (IL-12p19, IL-12 p35, IL-27p28) characteristic of the IL-6 superfamily and a beta subunit chain (IL-12p40, Ebi3) that shares homology with class I receptor chains. Janus kinases (Jak1, Jak2, Tyk2) are associated with the cytoplasmic tails of the receptors and binding of cognate receptors activate the Jaks and STATs (STAT1, STAT3, STAT4) resulting in transcription of targets genes that mediate biological activities. IL-35 appears to utilize unconventional receptors. In T cells it can utilize IL-12R 2/IL-12R 2, IL-12R 2/gp130 or gp130/gp130 and preferentially activate STAT1 and STAT4. In B cells, it utilizes IL-12R 2/IL-27 and activates STAT1 and STAT3. Jak utilization in response to IL-35 signaling in B cells has not been reported. IL27p28/IL12p40 is a novel bioengineered heterodimeric IL-12 cytokine generated by expression of IL-12p40 and IL-27p28 by use of a bicistronic vector. Jak utilization in response to ILp40/IL27p28 has not been reported and this cytokine inhibits gp130 and IL-27 signaling and does not activate STATs.

Figure 2

IL-6 superfamily share gp130 receptor subunit. Cytokines in the IL-6 superfamily include IL-6, ciliary neurotrophic factor (CNTF), oncostatin M (OSM), IL-11, Leukemia inhibitory factor (LIF) and they each bind to a receptor comprising of a common gp130 subunit and a cytokine-specific co-receptor (IL-6R, CNTFR, LIFR, OSMR, IL-11R). Signaling through the gp130 homodimer results in the phosphorylation of Janus kinases and preferential activation of STAT3 and to a lesser extent STAT1 and STAT5. IL-6R, IL-11R, and CNTFR are not necessarily membrane-anchored. and secretion of soluble receptor components may be a common attribute of all members. The soluble receptors are capable of ligand binding and signal transduction through gp130-containing dimers in a process referred to as trans-signaling.