Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells

Regulatory T (Treg) cells have a critical role in the control of immunity, and their diverse subpopulations may allow adaptation to different types of immune responses. In this study, we analyzed human Treg cell subpopulations in the peripheral blood by performing genome-wide expression profiling of 40 Treg cell subsets from healthy donors. We found that the human peripheral blood Treg cell population is comprised of five major genomic subgroups, represented by 16 tractable subsets with a particular cell surface phenotype. These subsets possess a range of suppressive function and cytokine secretion and can exert a genomic footprint on target effector T (Teff) cells. Correlation analysis of variability in gene expression in the subsets identified several cell surface molecules associated with Treg suppressive function, and pharmacological interrogation revealed a set of genes having causative effect. The five genomic subgroups of Treg cells imposed a preserved pattern of gene expression on Teff cells, with a varying degree of genes being suppressed or induced. Notably, there was a cluster of genes induced by Treg cells that bolstered an autoinhibitory effect in Teff cells, and this induction appears to be governed by a different set of genes than ones involved in counteracting Teff activation. Our work shows an example of exploiting the diversity within human Treg cell subpopulations to dissect Treg cell biology.

Section: Gene Expression Profiling Identifies Five Major Subgroups Ofsupporting

confidence: 87%

Diverse Gene Expression in Human Regulatory T Cell Subsets Uncovers Connection between Regulatory T Cell Genes and Suppressive Function

Hua

Davis

Hill

et al. 2015

“…In view of our results, Foxo1 can act as a repressor of RORgt, the master gene that unlocks the Th17 differentiation program. In human CCR6 + memory T cells, a similar mechanism might take place, as it has been recently reported that overexpression of FOXO1 decreases IL-17A (56). Activating Foxo1, with drugs acting either on pathways upstream this TF or directly controlling its activity, therefore offers a new means to control RORgt function and dampen Th17 responses.…”

Section: Pharmacological Modulation Of Foxo1 Activity Controls Th17 Dmentioning

confidence: 88%

Foxo1 Is a T Cell–Intrinsic Inhibitor of the RORγt-Th17 Program

Laine

Martin

Luka

et al. 2015

An uncontrolled exaggerated Th17 response can drive the onset of autoimmune and inflammatory diseases. In this study, we show that, in T cells, Foxo1 is a negative regulator of the Th17 program. Using mixed bone marrow chimeras and Foxo1-deficient mice, we demonstrate that this control is effective in vivo, as well as in vitro during differentiation assays of naive T cells with specific inhibitor of Foxo1 or inhibitors of the PI3K/Akt pathway acting upstream of Foxo1. Consistently, expressing this transcription factor in T cells strongly decreases Th17 generation in vitro as well as transcription of both IL-17A and IL-23R RORγt-target genes. Finally, at the molecular level, we demonstrate that Foxo1 forms a complex with RORγt via its DNA binding domain to inhibit RORγt activity. We conclude that Foxo1 is a direct antagonist of the RORγt-Th17 program acting in a T cell–intrinsic manner.

“…The PI3K/AKT pathway has been associated with Th17 cell development (38) and with IL-17 expression by CCR6 + human memory T cells (39). Thus, targeting MAPK/ERK along with the JAK/ PI3K/AKT pathways may be beneficial for inhibiting Th17-mediated bone loss.…”

Section: Discussionmentioning

confidence: 99%

Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss

Azreq

Arseneault

Boisvert

et al. 2015

Th17 cells are critical effectors in inflammation and tissue damage such as bone erosion, but the mechanisms regulating their activation in this process are not fully understood. In this study, we considered the cooperation between cytokine receptors and integrin pathways in Th17-osteoclast function. We found that human Th17 cells coexpress IL-7R and the collagen-binding integrin α2β1 (CD49b), and IL-7 increases their adhesion to collagen via α2β1 integrin. In addition, coengagement of the two receptors in human Th17 cells cooperatively enhanced their IL-17 production and their osteoclastogenic function. The functional cooperation between IL-7R and α2β1 integrin involves activation of the JAK/PI3K/AKT (protein kinase B) and MAPK/ERK pathways. We also showed that IL-7–induced bone loss in vivo is associated with Th17 cell expansion. Moreover, blockade of α2β1 integrin with a neutralizing mAb inhibited IL-7–induced bone loss and osteoclast numbers by reducing Th17 cell numbers in the bone marrow and reducing the production of IL-17 and the receptor activator of NF-κB ligand. Thus, the cooperation between IL-7R and α2β1 integrin can represent an important pathogenic pathway in Th17-osteoclast function associated with inflammatory diseases.