Unique Phenotype of Human Tonsillar and In Vitro-Induced FOXP3+CD8+ T Cells

Abstract

Forkhead box p3 (FOXP3) is known to program the acquisition of suppressive capacities in CD4؉ regulatory T cells (Treg), whereas its role in CD8 ؉ T cells is unknown. The current study investigates whether FOXP3 also acts as a Treg master switch in peripheral blood and tonsillar CD8 ؉ T cells. FOXP3 is a transcriptional regulator, repressing proinflammatory cytokine expression while inducing the expression of immune regulatory cytokines and Treg markers (8). By interacting with other transcription factors and chromatin modifying enzymes, FOXP3 induces epigenetic modifications that lead to the generation of Treg cells (9). Thus, FOXP3 acts as a master switch factor for Treg development similar to T-bet, GATA3, and retinoic acid receptor-related orphan receptor ␥t (ROR␥t; also known as RORC2) for the Th1, Th2, and Th17 cells, respectively. Initially, FOXP3 expression was detected only in CD25 high CD4 ϩ T cells in mice and humans (10 -13). However, its transgenic expression conferred suppressive activity to CD25 Ϫ CD4 ϩ T cells as well as to the CD8 ϩ subset of T cells (13,14). Whereas FOXP3 ϩ CD8 ϩ T cells constitute a minuscule fraction of circulating CD8 ϩ T cells in human blood, polyclonal activation in vitro induces expression of FOXP3 (15)(16)(17)(18)(19). Currently, it is not known how human FOXP3 ϩ CD8ϩ Treg cells develop in vivo and whether they possess suppressive activity.The development of anti-inflammatory CD4 ϩ Treg cells and the expression of their lineage-specific transcription factor FOXP3 has been shown to require . Surprisingly, the development of the proinflammatory Th17 cells and the expression of their suggested lineage-specific transcription factor ROR␥t depend also on TGF-␤ (21-23). In contrast to Treg cells, Th17 cell development requires the cytokine IL-6 in addition to TGF-␤, especially for the expression of the Th17 signature cytokine IL-17A (21). TGF-␤ is abundantly expressed in the MALT and plays a critical role in oral tolerance induction. As part of the MALT, palatine tonsils are located at the gateway of the respiratory and alimentary tracts where they are continually exposed to airborne and ingested Ags (24). Since the discrimination between harmless and harmful potential pathogens takes place in tonsils, they are a key site of effective immunity or tolerance. Whether CD8 ϩ Treg cells are present in tonsils and participate in the regulation of their immune response is currently unknown.In this study, we identify a FOXP3 ϩ CD8 ϩ T cell population in human tonsils that is predominantly CD25Ϫ and includes some IFN-␥-, TNF-␣-, and IL-17A-expressing cells. In vitro stimulation of naive CD8ϩ T cells induces FOXP3 ϩ CD8 ϩ T cells exhibiting The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.1 This work was supported in part by a Marie Curie Intra-European Fellowship from the European Commission (to K.S.) and Swiss Na...

Differentiation of human thymic regulatory T cells at the double positive stage

“…Although FOXP3 1 CD8SP did not share the activated phenotype observed in FOXP3 1 DP and CD4SP cells, previous studies have shown that CD8SP cells purified on the basis of CD25 expression have suppressive properties [14]. FOXP3 1 CD8 1 T cells are rarely found in the peripheral blood [34,35], but CD25 1 FOXP3 1 CD8 1 T cells have been identified in normal colonic tissue and were found to be increased in colorectal cancer tissue [34]. Interestingly, we found that the vast majority of FOXP3 1 CD8SP cells in the human thymus express CD103, suggesting that they have the capacity to preferentially home to the mucosa.…”

“…3B). The observation of high levels of expression of a mucosal homing molecule within FOXP3 1 CD8SP is particularly relevant, since FOXP3 1 CD8 T cells are rarely found in human peripheral blood and have been described in the colon mucosa [34,35]. Information Fig.…”

Systemic and local human papillomavirus 16‐specific T‐cell immunity in patients with head and neck cancer

“…Although the transcription factor Foxp3 is mainly reported in CD4þ regulatory T cells we found CD8þCD25þFoxP3 high T cells in TIL and in CD8þ T-cell clones derived from the tonsil region. Siegmund et al describe this phenotype to be uniquely present in human tonsil tissue, 41 however their presence was also demonstrated in human prostate cancer. 42 Whether these T cells with tolerogenic phenotype are a reflection of suppressed local immunity or part of an ongoing adaptive immune response can not be concluded from this data.…”

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

“…Moreover, we also surprisingly observed higher levels of FOXP3 + CD8 + T cells in the lamina propria of MHCII −/− →WT mice, which now more broadly suggests that MHCII-dependent antigen presentation limits the induction of atypical CD8 + T-cell subsets in vivo. Little is currently known about FOXP3 + CD8 + T cells; however, recent studies have suggested that these cells retain regulatory function and can express surface markers generally associated with CD4 + Treg cells such as CTLA-4 [36,37]. Studies aiming at further understanding the transcriptional program that regulates the differentiation of IL-17 + and FOXP3 + CD8 + T cells both in vitro and in vivo would therefore be of interest.…”