The effects of IL-6 on CD4 T cell responses

Abstract

Cytokines have long been known to profoundly influence the adaptive immune response by determining CD4 T cell differentiation. Although IL-6 has been initially characterized as a B cell growth factor and inducer of antibody production research from our lab and others has revealed over the last years that IL-6 also plays a significant role in CD4 T cell differentiation. This review highlights the variety of ways in which IL-6 affects CD4 effector functions and how this may contribute to different types of diseases.

Figure 1

Molecular mechanism of IL-6 induced IL-4 production. Stimulation by IL-6 activates the transcription factors STAT3 through JAKs and C/EBP through the ras-ERK MAPK cascade. STAT3 upregulates c-maf expression while C/EBP may mediate upregulation of NFATc2. c-maf and NFATc2 activate in a potentially synergistic manner the expression of IL-4. Autocrine production of IL-4 will subsequently promote Th2 differentiation.

Figure 2

IL-6 exerts its effects on cytokine production through a diverse set of key molecules. Upregulation of SOCS1 expression inhibits IFNγ signals thereby diminishing additional IFNγ production. IL-4 production is mediated through the induction of NFATc2 and c-maf expression. STAT3 directly regulates IL-6 induced IL-21 expression, which therefore precedes expression of the other cytokines. Simultaneous stimulation through IL-6 and TGFβ induces high level expression of RORγt which mediates IL-17 production.

Figure 3

Contribution of IL-6 to T helper cell differentiation and subsequent cytokine production by various T cell subsets. IL-6 exerts inhibitory activity towards Th1 and T regulatory (Treg) differentiation/function and promotes Th2 and Th17 differentiation either alone (Th2) or together with TGFβ (Th17). The role of IL-6 in T follicular helper (Tfh) cell differentiation is suggested due to its specific upregulation of IL-21 in naïve CD4 T cells.