Differences in CD44 Surface Expression Levels and Function Discriminates IL-17 and IFN-γ Producing Helper T Cells

CD44 is a prominent activation marker which distinguishes memory and effector T cells from their naïve counterparts. It also plays a role in early T cell signaling events as it is bound to the lymphocyte-specific protein kinase and thereby enhances T cell receptor signalling. Here, we investigated whether IFN-γ and IL-17 producing T helper cells differ in their CD44 expression and their dependence of CD44 for differentiation. Stimulation of CD4(+) T cells with allogeneic dendritic cells resulted in the formation of three distinguishable populations: CD44(+), CD44(++) and CD44(+++). In vitro and in vivo generated allo-reactive IL-17 producing T helper cells were mainly CD44(+++) as compared to IFN-γ(+) T helper cells, which were CD44(++). This effect was enhanced under polarizing conditions. T helper 17 polarization led to a shift towards the CD44(+++) population, whereas T helper 1 polarization diminished this population. Furthermore, blocking CD44 decreased IL-17 secretion, while IFN-γ was barely affected. Titration experiments revealed that low T cell receptor and CD28 stimulation supported T helper 17 rather than T helper 1 development. Under these conditions CD44 could act as a co-stimulatory molecule and replace CD28. Indeed, rested CD44(+++)CD4(+) T cells contained already more total and especially phosphorylated zeta-chain-associated protein kinase 70 as compared to CD44(++) cells. Our results support the notion, that CD44 enhances T cell receptor signaling strength by delivering lymphocyte-specific protein kinase, which is required for induction of IL-17 producing T helper cells.