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

PLoS One. 2015 Jul 14;10(7):e0132479. doi: 10.1371/journal.pone.0132479. eCollection 2015.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD28 Antigens / metabolism
  • CD3 Complex / pharmacology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation* / drug effects
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Interferon-gamma / biosynthesis*
  • Interleukin-17 / biosynthesis*
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Male
  • Mice
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / metabolism*

Substances

  • CD28 Antigens
  • CD3 Complex
  • Hyaluronan Receptors
  • Interleukin-17
  • Receptors, Antigen, T-Cell
  • Interferon-gamma

Grant support

This work was supported by the grant Transregio 52 (TR52), from the German Research Foundation (DFG) to B.S. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.