Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo

Abstract

Regulatory T cells (Tregs) play a fundamental role in the suppression of different immune responses; however, compartments at which they exert suppressive functions in vivo are unknown. Although many groups have described the presence of Tregs within inflammatory sites, it has not been shown that inflamed tissues are, indeed, the sites of active suppression of ongoing immune reactions. Here, by using ␣ E ؉ effector/memory-like Tregs from fucosyltransferase VII-deficient animals, which lack E/P-selectin ligands and fail to migrate into inflamed sites, we analyzed the functional importance of appropriate Treg localization for in vivo suppressive capacity in an inflammation model. Lack of suppression by Tregs deficient in E/P-selectin ligands demonstrates that immigration into inflamed sites is a prerequisite for the resolution of inflammatory reactions in vivo because these selectin ligands merely regulate entry into inflamed tissues. In contrast, control of proliferation of naive CD4 ؉ T cells during the induction phase of the immune response is more efficiently exerted by the naive-like ␣ E ؊ CD25 ؉ Treg subset preferentially recirculating through lymph nodes when compared with its inflammation-seeking counterpart. [21][22][23] or inflamed intestine in induced colitis. 24 Moreover, a few studies demonstrated the capacity of Tregs to down-regulate established immune reactions, [24][25][26][27] suggesting that regulation might also act locally in the inflammatory environment.The resulting questions-in which compartment suppression by Tregs occurs and how critical is an appropriate localization of Tregs for their in vivo suppressive capacity-have not been addressed directly, as yet.We have previously shown that by use of the marker ␣ E (CD103) the Treg compartment can be subdivided into a lineage or differentiation stage of natural, naive-like ␣ E Ϫ CD25 ϩ Tregs and into that of ␣ E ϩ Tregs (either CD25 ϩ or CD25 Ϫ ) with the phenotype of effector/memory cells. 28,29 Whereas ␣ E Ϫ CD25 ϩ Tregs express high levels of CD62L and CCR7 and recirculate through lymph nodes, effector/memory-like ␣ E ϩ Tregs express high levels of inflammatory chemokine receptors and multiple adhesion molecules as well as selectin ligands and efficiently migrate into inflamed sites. Importantly, the integrin ␣ E ␤ 7 itself only seems to play a role for the retention within peripheral tissues, 30,31 but is not involved in the extravasation process of CD4 ϩ T lymphocytes. 32 In the present study it rather serves as a surrogate marker to identify inflammation-seeking Tregs.Migration of CD4 ϩ effector T cells into inflamed skin has been previously reported to be critically dependent on the expression of selectin ligands, 33,34 which bind to the partially redundantly acting E-and P-selectins, expressed almost exclusively on endothelium of For personal use only. on May 9, 2018. by guest www.bloodjournal.org From inflamed tissues. Biosynthesis of functional selectin ligands is mediated by several glycosyltransferases. 35 Among these enzymes, fuco...

Distinctive role of CCR7 in migration and functional activity of naive‐ and effector/memory‐like Treg subsets

“…4A). In the presence of a E -CD25 + Treg from DO11.10 (WT) mice, proliferation of naive T cells was strongly suppressed and the majority of CFSE-labeled cells remained undivided, in line with our previous data [13]. However, naive-like Treg from DO11.10ÂCCR7 -/-(KO) mice displayed no suppressive activity within the draining LN and a marked number of CFSE-labeled target cells had completed three to seven cell divisions, similar to what has been observed in the absence of transferred, antigen-specific Treg (Fig.…”

“…We could demonstrate that recirculating, naive-like Treg act as central regulators within lymphoid tissues during the priming phase of immune responses [13]. This is conceivable since Treg-mediated suppression requires direct cell-cell contact [14].…”

“…We recently demonstrated that naive-like a E -CD25 + Treg efficiently migrate into LN to control antigenspecific naive T cell proliferation [13]. (KO) and DO11.10 (WT) mice.…”

“…3 and [3]), is of functional importance for the exit from inflamed, peripheral tissues. Therefore, we employed a Th1-mediated antigen-specific DTH model, in which we had previously demonstrated that only inflammation-seeking a E + Treg were capable of suppressing skin inflammation [13].…”

“…On the other hand, inflammation-seeking, effector/memory-like Treg are specialized to control ongoing immune responses directly within the inflammatory environment. Indeed, expression of trafficking receptors such as selectin ligands and chemokine receptors on effector/memorylike Treg subsets critically influences their in vivo suppressive capacity in inflammation [13,[15][16][17], suggesting that appropriate localization is indispensable for Treg function [2].…”