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

Abstract

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.

Mass cytometry identifies distinct CD4+ T cell clusters distinguishing HIV-1–infected patients according to antiretroviral therapy initiation

“…These T cell populations also displayed a high and consistent expression of CD44. CD44 had originally been described as an adhesion molecule binding to hyaluronic acid (HA) and additional ligands and has gained attention recently as an activation marker distinguishing memory and effector T cells from their naive counterparts (17). The low expression of CD45RA in these 12 clusters, accompanied by high expression of CD27, CD28, CD127, and CD44, indicate that these clusters largely represent memory T cells.…”

Cyp1b1‐mediated suppression of lymphoid progenitors in bone marrow by polycyclic aromatic hydrocarbons coordinately impacts spleen and thymus: a selective role for the Ah Receptor

“…S3B). The proportions of high, intermediate and low CD44 provide a measure of IL-17 and IFN-c secretion in the CD4 population (Schumann et al 2015), whereas CD44 and CD62L positive expression provides a measure of memory status in the T8+ population. Apart from modest decreases in CD44 expression, the proportions of these populations were also largely unaffected by the PAHs.…”

The methyltransferase DOT1L limits activation and the Th1 program in CD4+T cells during infection and inflammation

“…Our transfer experiments further showed that the activated phenotype of CD4 + T cells in the absence of DOT1L was not cell intrinsic but dependent on the T cell lymphopenic conditions. Despite high levels of CD44 in the absence of DOT1L and reports that high CD44 expression leads to a Th17 phenotype (Schumann et al, 2015), CD4 + T cells in the absence of DOT1L produced increased IFN-γ over IL-17. As we observed decreased expression of CD5, and increased expression of Nur77 and CD69 in the absence of DOT1L as markers of TCR activation, our finding of a Th1-biased development of CD4 + T cells is consistent with reports that stronger TCR signalling is correlated to induction of Th1 cells, even in the presence of Th2 promoting conditions (Constant et al, 1995;Hosken et al, 1995;van Panhuys et al, 2014).…”