IL-2Rβ–Dependent Signaling and CD103 Functionally Cooperate To Maintain Tolerance in the Gut Mucosa

Abstract

A network of mechanisms operates to maintain tolerance in the gut mucosa. Although CD103 marks many lymphoid cells within the gut, its direct functional role in intestinal tolerance is poorly understood. CD103 may be part of a redundant pathway as CD103−/− mice do not exhibit autoimmunity. To reduce such redundancy, CD103−/− mice were crossed to mice (designated Y3) whose T cells expressed a mutant IL-2Rβ chain that lowers IL-2R signaling. Unlike overtly healthy Y3 mice, all Y3/CD103−/− mice rapidly developed severe colitis. The large intestine of these mice contained an increase in CD4+ Th1 and Th17 effector cells and a reduced ratio of regulatory T cells (Tregs). Importantly, colitis was effectively prevented by the transfer of wild type (WT) Tregs into Y3/CD103−/− mice. Impaired intestinal tolerance was not attributed to an obvious lack of CD103-dependent gene regulation or intestinal homing/retention by Tregs nor a lack of functional activities typically associated with CD103+ dendritic cells (DCs), such as peripheral induced Treg (pTreg) development or imprinting CCR9 and α4β7 homing molecules on Treg and T effector cells. Transcriptome analysis of Tregs was consistent with altered homeostasis due to impaired IL-2Rβ-dependent signaling with minimal dysregulation added by the absence of CD103. Rather the absence of CD103 functioned to alter the localization of the cells within the gut microenvironment that may alter Treg homeostasis. Thus, IL-2Rβ-dependent signaling and CD103 normally cooperate through distinctive processes to promote Treg homeostasis and immune tolerance.

CD83 expression is essential for Treg cell differentiation and stability

“…CD103 is encoded by the ITGAE gene and is a ligand for E-cadherin, an adhesion molecule found on epithelial cells. It is known that CD103 mediates T cell retention in the epithelial compartment and is a well-established marker for murine effector/memory-like Tregs that have been activated in vivo by antigen (43). Interestingly, in cKO-derived Tregs IL-2RA (CD25) was found to be downregulated.…”

The CD83 Molecule – An Important Immune Checkpoint

“…Further, KLRG1 is a late differentiation marker on T cells and the development of terminally differentiated KLRG1 + Tregs also depends on IL-2 signaling (40). Likewise, the CD103 molecule, a ligand for E-cadherin, has also been described as a marker for murine "effector memory"-like Tregs especially in the intestinal mucosa (42). Notably, CD83 expression in Tregs is not essential for Foxp3 expression (38).…”

Impact of Immune-Modulatory Drugs on Regulatory T Cell

“…The resulting reduction of cosimulation increases the threshold for Tconv activation. During an active immune response, TCR and cytokine stimulations induce Treg trafficking to inflammatory sites where they use a broader array of suppressive mechanisms to dampen inflammation and limit collateral tissue damage 13 . Activated Treg can also induce new pTreg with distinct alloantigen specificity leading to an “infectious” spread of tolerance 14 .…”