Integrin α E (CD103) Is Involved in Regulatory T-Cell Function in Allergic Contact Hypersensitivity

Abstract

Murine contact hypersensitivity (CHS) is a dendritic cell (DC)-dependent T-cell-mediated inflammation with CD8+ T cells as effectors and CD4+ T cells as regulators (Treg cells) that models human allergic contact dermatitis. The integrin αE(CD103) is expressed by some T-cell and DC subsets and has been implicated in epithelial lymphocyte localization, but its role in immune regulation remains enigmatic. We have identified a function for CD103 in the development of cutaneous allergic immune responses. CHS responses, but not irritant contact dermatitis, were significantly augmented in CD103-deficient mice in hapten-challenged skin. Phenotype and function of skin DCs during sensitization were normal, whereas adoptive transfer experiments revealed that the elevated CHS response in CD103-deficient mice is transferred by primed T cells and is independent of resident cells in recipient mice. While T-cell counts were elevated in challenged skin of CD103-deficient mice, the FoxP3 expression level of CD4+CD25+ Treg cells was significantly reduced, indicating impaired functionality. Indeed, Treg cells from CD103-deficient mice were not able to suppress CHS reactions during the elicitation phase. Further, CD103 on FoxP3+ Treg cells was involved in Treg retention to inflamed skin. These findings indicate an unexpected dichotomous functional role for CD103 on Treg cells by modulating FoxP3 expression.

Transient epidermal barrier deficiency and lowered allergic threshold in filaggrin‐hornerin (FlgHrnr−/−) double‐deficient mice

“…Furthermore, CD103‐expressing Treg exert the strongest suppressive activity . As a consequence, during skin inflammation, Treg from CD103‐deficient mice express FoxP3 to a lesser extent and are not able to regulate cutaneous immune response in a CHS model . In line, we found lesser expression of FoxP3 in FlgHrnr −/− mice indicative for an impaired Treg function.…”

DOCK8 enforces immunological tolerance by promoting IL-2 signaling and immune synapse formation in Tregs

“…DOCK8-deficient Tregs demonstrated decreased expression of several IL-2-regulated genes that included Foxp3 and Il2ra, consistent with impaired IL-2-driven STAT5 phosphorylation. There was also decreased expression of several transcription factors that affect Treg stability and subset development (62,67,68,72,74,82,83). This may be relevant to the rampant Th1/Th17 intestinal inflammation observed in mice.…”

A Yin and Yang in Epithelial Immunology: The Roles of the αE(CD103)β7 Integrin in T Cells

“…Indeed, a recent investigation demonstrated Smad3-and nuclear-factor-ofactivated-T-cell-binding enhancer elements within ITGAE, in addition to a Smad3-binding promoter site (Mokrani et al, 2014). Quite intriguingly, the forkhead-box-P3 (FoxP3) gene features similar Smad3-and nuclear-factor-of-activated-T-cell-enhancer elements (Tone et al, 2008), thus providing a rather compelling circumstantial explanation for the higher FoxP3 expression in CD103 þ /CD4 þ T reg (Figure 1b) (Braun et al, 2015;Huehn et al, 2004). Although it has not been formally ruled out that a E (CD103)b 7 signaling leads to downstream FoxP3 induction, it appears that a E (CD103)b 7 expression is concordantly linked to FoxP3 expression owing to their shared response to Smad3 and nuclear-factor-ofactivated-T-cell signaling in TGF-b-governed milieus.…”

“…Evidence for binding to other putative epithelial or mesenchymal ligands is indirect and candidate ligands still remain elusive (Brown et al, 1999;Jenkinson et al, 2011;Strauch et al, 2001). However, a nonepithelial ligand for a E (CD103)b 7 would provide a convenient explanation for the dominance of CD103 þ /CD4 þ regulatory T cells (T reg ) in the murine dermis, as well as the high frequency of a E (CD103)b 7 -expressing cytotoxic T-lymphocytes (CTLs) within the intestinal lamina propria (Braun et al, 2015;Schön et al, 1999;Suffia et al, 2005).…”