Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development

Abstract

The generation of natural regulatory T cells (nTregs) is crucial for the establishment of immunologic self-tolerance and the prevention of autoimmunity. Still, the origin of nTregs and the mechanisms governing their differentiation within the thymus are poorly understood, particularly in humans. It was recently shown that conventional dendritic cells (cDCs) in human thymus were capable of inducing nTreg differentiation. However, the function of plasmacytoid DCs (pDCs), the other major subset of thymic DCs, remains unknown. Here we report that pDCs resident in the human thymus, when activated with CD40 ligand (CD40L) plus interleukin-3, efficiently promoted the generation of CD4 ؉ CD25 ؉ Foxp3 ؉ nTregs from autologous thymocytes. The progenitors of these nTregs were selectively found within CD4 ؉ CD8 ؉ thymocytes that had accomplished positive selection, as judged by their CD69 hi TCR hi phenotype. Supporting the involvement of the CD40-CD40L pathway in pDC-induced nTreg generation, we show that positively selected CD4 ؉ CD8 ؉ progenitors specifically transcribed CD40L in vivo and upregulated CD40L expression on T-cell receptor engagement, thereby promoting the activation of pDCs. Finally, evidence is provided that nTregs primed by pDCs displayed reciprocal interleukin-10/transforming growth factor-␤ cytokine expression profiles compared with nTregs primed by cDCs. This functional diversity further supports a nonredundant tolerogenic role for thymic pDCs in the human thymus. (Blood. 2010;115(26):5366-5375) IntroductionDendritic cells (DCs) are highly specialized antigen-presenting cells (APCs) that are crucial in the regulation of innate and adaptive immunity. DCs respond to danger signals by antigen uptake, maturation, and induction of antigen-specific immune responses in secondary lymphoid organs. 1,2 In addition, tissue DCs are able to present antigen in a tolerogenic fashion, leading to anergy or deletion of potentially self-reactive T cells, or inducing the generation of regulatory T cells (Tregs). [3][4][5][6] Tregs play a key role in the control of immune homeostasis and immunologic tolerance and are crucial to protect against fatal autoimmunity throughout life. Tregs also regulate or suppress other classes of immune responses, such as allograft rejection, allergy, tumor immunity, and responses to microbes. 7,8 Thus, there is great interest in understanding how do Tregs develop.During thymopoiesis, nearly all positively selected CD4 ϩ CD8 ϩ double-positive (DP) thymocytes carrying high-affinity T-cell receptors (TCRs) for self-peptide-major histocompatibility complexes are eliminated by a mechanism of clonal deletion that ensures central tolerance. 6 Self-reactive thymocytes that escape clonal deletion undergo an alternative process of nondeletional tolerance that involves their positive selection and further differentiation into immunosuppressive CD4 ϩ T cells, termed natural Tregs (nTregs). [8][9][10][11] In addition, Tregs can be induced in the periphery (iTregs) from CD4 ϩ T lymphocytes. 4 Generation o...

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

“…In agreement, it was recently suggested that human Treg-cell progenitors may selectively reside within mature DP thymocytes expressing high levels of CD69 and TCR-ab, since these cells develop into CD4SP Treg cells in response to activated autologous plasmacytoid and myeloid DCs [40], although not excluding the possibility of FOXP3 induction at the SP stages [41,42]. Additionally, our multiple regression analyses show a significant statistical dependency of the FOXP3 1 DP and SP populations, further supporting their direct precursor-product association.…”

Lectin-like Receptor Ly49s3 on Dendritic Cells Contributes to the Differentiation of Regulatory T Cells in the Rat Thymus

“…For example, in humans, conventional DCs (cDCs) activated by thymic stromal lymphopoietin (TSLP) from epithelial cells of Hassall's corpuscles have been reported to induce the differentiation of CD4 + CD25 2 thymocytes into Tregs within the thymic medulla (6). More recently, TSLP activated another main subset of DCs, plasmacytoid DCs (pDCs), which have also been demonstrated to mediate Treg generation from CD4 + CD25 2 thymocytes in the medulla of the human thymus (9,10). After being activated with TSLP, DCs upregulate the expression of MHC class II molecules and costimulatory molecules, such as CD80 and CD86 (11,12), enhancing signaling events between DCs and thymocytes.…”

“…It has also been reported that human thymic pDCs regulate the nTreg developmental process (9,10). Therefore, it remains to be clarified whether rat thymic pDCs are involved in nTreg differentiation and express the Ly49 family genes, including Ly49s3.…”

Factors Contributing to HIV-1 Induced Pathogenesis in the Human Thymus

“…Treg cells are continuously produced in the thymus as a distinct lineage contiguous with peripheral blood Treg cells (reviewed in Sakaguchi, 2005)). There is recent evidence that thymic pDC play a role in the development of nTreg (Hanabuchi et al, 2010;Martin-Gayo et al, 2010). Both pDC and Treg cells are located closely together in the thymic medulla, which may suggest interactions between them (Martin- Gayo et al, 2010;Watanabe et al, 2005).…”

“…There is recent evidence that thymic pDC play a role in the development of nTreg (Hanabuchi et al, 2010;Martin-Gayo et al, 2010). Both pDC and Treg cells are located closely together in the thymic medulla, which may suggest interactions between them (Martin- Gayo et al, 2010;Watanabe et al, 2005). In addition to the induction of Treg cells by cDC activated with the IL-7 like cytokine thymic stromal lymphopoietin (TSLP) , FoxP3 + Treg cells can also be induced in the thymus by pDC after these have been stimulated with TSLP (Hanabuchi et al, 2010).…”