CD44 Costimulation Promotes FoxP3+ Regulatory T Cell Persistence and Function via Production of IL-2, IL-10, and TGF-β

Abstract

Work by our group and others has demonstrated a role for the extracellular matrix receptor CD44 and its ligand hyaluronan in CD4+CD25+ regulatory T cell (Treg) function. Herein, we explore the mechanistic basis for this observation. Using mouse FoxP3/GFP+ Treg, we find that CD44 costimulation promotes expression of FoxP3, in part through production of IL-2. This promotion of IL-2 production was resistant to cyclosporin A treatment, suggesting that CD44 costimulation may promote IL-2 production through bypassing FoxP3-mediated suppression of NFAT. CD44 costimulation increased production of IL-10 in a partially IL-2-dependent manner and also promoted cell surface TGF-β expression. Consistent with these findings, Treg from CD44 knockout mice demonstrated impaired regulatory function ex vivo and depressed production of IL-10 and cell surface TGF-β. These data reveal a novel role for CD44 cross-linking in the production of regulatory cytokines. Similar salutary effects on FoxP3 expression were observed upon costimulation with hyaluronan, the primary natural ligand for CD44. This effect is dependent upon CD44 cross-linking; while both high-molecular-weight hyaluronan (HA) and plate-bound anti-CD44 Ab promoted FoxP3 expression, neither low-molecular weight HA nor soluble anti-CD44 Ab did so. The implication is that intact high-molecular weight HA can cross-link CD44 only in those settings where it predominates over fragmentary LMW-HA, namely, in uninflamed tissue. We propose that intact but not fragmented extracellular is capable of cross-linking CD44 and thereby maintains immunologic tolerance in uninjured or healing tissue.

Inhibition of hyaluronan synthesis restores immune tolerance during autoimmune insulitis

“…Conversely, this inhibition was relieved by inhibition of HA synthesis with 4-MU. Together with our earlier work (26,27), these data suggest that CD44 restricts the expansion of Tregs but promotes their phenotypic stability. This is the inverse of TLR2 agonists, which are known to promote Treg induction but inhibit suppression (28,29).…”

“…Mouse leukocyte populations were isolated from ILNs, MLNs, PLNs, and spleens as previously described (26). Mouse flow cytometry experiments used the following fluorochrome-labeled antibodies from BD Biosciences: CD3e (145-2C11), CD4 (RM4-5), CD25 (PC61.5), and CD44 (IM7).…”

The Tumor Suppressor CYLD Controls the Function of Murine Regulatory T Cells

“…3B). Previously, it has been reported that the expression of CD44 is essential for the regulatory function of Foxp3 + Tregs, as Tregs isolated from CD44 knockout mice displayed impaired regulatory function accompanied by decreased production of anti-inflammatory cytokines (32). As shown in the histogram of Fig.…”

Deficiency of IL-22 Contributes to a Chronic Inflammatory Disease: Pathogenetic Mechanisms in Acne Inversa

“…Different factors may play a role, including: nucleotide polymorphisms of the IL-10 gene (56,57); accumulation of regulatory T cells (Foxp3-positive cells), of Tr1 cells (IL-10-secreting Foxp3-negative cells), or of highly IL-10-producing APCs (58)(59)(60)(61)(62)(63)(64); and the enhanced presence of IL-10-inducing cytokines. Having investigated the latter possibility, the positive correlation between lesional IL-10 and IL-1b levels found in the current study may indeed point to a role of IL-1b in upregulating IL-10.…”