Enriched CD161<sup>high</sup>CCR6<sup>+</sup>γδ T Cells in the Cerebrospinal Fluid of Patients With Multiple Sclerosis

Schirmer, Lucas; Rothhammer, Veit; Hemmer, Bernhard; Korn, Thomas

doi:10.1001/2013.jamaneurol.409

Cited by 68 publications

(45 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…gdT17 cells have most recently been shown to participate in the immunopathology of a variety of inflammatory diseases in epithelial barrier tissues, including inflammatory bowel disease, psoriasis, and asthma (11,14,15), but also in spondylarthropathies and CNS inflammation in mouse models (1,16) and in humans (17)(18)(19). Because the presence of gdT17 cells in certain tissues might set the threshold for these tissues to respond directly to pathogen-associated molecular patterns and indirectly to the proinflammatory cytokine IL-23, the regulation of gdT17 cell populations during homeostasis and in inflammation is highly relevant in the context of immune interventions in autoimmune diseases, chronic inflammation, and inflammation associated with malignant disease.…”

mentioning

confidence: 99%

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

Muschaweckh

Petermann

Korn

2017

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

γδT17 cells are a subset of γδ T cells committed to IL-17 production and are characterized by the expression of IL-23R and CCR6 and lack of CD27 expression. γδT17 cells are believed to arise within a narrow time window during prenatal thymic development. In agreement with this concept, we show in this study that adult Rag1−/− recipient mice of Il23rgfp/+ (IL-23R reporter) bone marrow selectively lack IL-23R+ γδT17 cells. Despite their absence in secondary lymphoid tissues during homeostasis, γδT17 cells emerge in bone marrow chimeric mice upon induction of skin inflammation by topical treatment with imiquimod cream (Aldara). We demonstrate that IL-1β and IL-23 together are able to promote the development of bona fide γδT17 cells from peripheral CD122−IL-23R− γδ T cells, whereas CD122+ γδ T cells fail to convert into γδT17 cells and remain stable IFN-γ producers (γδT1 cells). IL-23 is instrumental in expanding extrathymically generated γδT17 cells. In particular, TCR-Vγ4+ chain–expressing CD122−IL-23R− γδ T cells are induced to express IL-23R and IL-17 outside the thymus during skin inflammation. In contrast, TCR-Vγ1+ γδ T cells largely resist this process because prior TCR engagement in the thymus has initiated their commitment to the γδT1 lineage. In summary, our data reveal that the peripheral pool of γδ T cells retains a considerable degree of plasticity because it harbors “naive” precursors, which can be induced to produce IL-17 and replenish peripheral niches that are usually occupied by thymus-derived γδT17 cells.

show abstract

mentioning

confidence: 99%

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

Muschaweckh

Petermann

Korn

2017

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Similarly, ␥␦17 cells may differentially express the IL-4R, and STAT6 may distinctly regulate ␥␦17 cell cytokine production in other sites where ␥␦ T cells are prevalent, such as in the gut or skin. Increasing STAT6 activity could represent an immunotherapeutic strategy to treat ␥␦17-mediated diseases, such as psoriasis and multiple sclerosis, by decreasing inflammatory IL-17A production (37,38). In contrast, STAT6 is expressed at high levels in patients with asthma (20), and phase II randomized clinical trials have investigated the effects of blocking IL-4 and IL-13 signaling.…”

Section: Discussionmentioning

confidence: 99%

STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection

et al. 2016

View full text Add to dashboard Cite

A pproximately 50% of the intraepithelial lymphocyte population is composed of ␥␦ T cells, which constitute a critical first line of defense against bacterial and fungal pathogens (1). In contrast to adaptive ␣␤ T cells, ␥␦ T cells are capable of immediate cytokine release, providing an initial innate layer of protection at mucosal surfaces while influencing the development of subsequent adaptive responses (2, 3). ␥␦17 cells are a subset of ␥␦ T cells that produce large quantities of interleukin-17A (IL-17A), a cytokine crucial to antibacterial and antifungal defense (4). ␥␦17 cells also produce high levels of IL-17A in various models of inflammation and autoimmunity, including experimental autoimmune encephalitis, ischemic brain injury, and psoriasis (2, 3, 5-7). While these data highlight the importance of understanding how ␥␦17 cell function is regulated, this process remains poorly understood.␥␦17 cell function is controlled by multiple immune cell populations and soluble molecules, particularly cytokines. Within 4 to 8 h in the presence of the inflammatory cytokines IL-23 and IL-1␤, ␥␦17 cells secrete IL-17A without the need for T cell receptor (TCR) engagement (2). ␥␦17 cells constitutively express IL-23 receptor (IL-23R) and IL-1R1, providing for an efficient mechanism to induce rapid effector cytokine production. A recent study showed that the serine/threonine kinase Sgk1 is a novel, critical regulator of IL-23R expression (8).Studies from our group and others have established that STAT6 negatively regulates IL-17A expression in Th17 cells (9-13). By extension, we hypothesized that STAT6 also inhibits innate ␥␦17 cell cytokine secretion. STAT6 is a transcription factor important for Th2 differentiation, inhibiting Th1 differentiation and activating the B cell response (14). IL-4 signals through both the type I IL-4 receptor (IL-4R), which consists of IL-4R␣ and the common ␥-chain, and the type II IL-4R, which consists of IL-4R␣ and IL-13R␣, while IL-13 signals through only the type II IL-4R (15, 16). IL-4 binds to the IL-4R␣ subunit and IL-13 binds to the IL-13R␣ subunit of the IL-4 heterodimer receptor with high affinity, leading to the phosphorylation of STAT6 (17,18). STAT6 is expressed at high levels in the settings of parasitic infections (19) and asthma, during which STAT6 induces Th2 differentiation, IgE antibody class switching, goblet cell metaplasia, alternative macrophage activation, mucus expression, and airway remodeling (20). Thus, STAT6 attenuation of ␥␦17 cell function may impair host defenses against bacterial and fungal infections in people with asthma or parasitic infections.We found that ␥␦17 cells expressed the type I IL-4R, and that IL-4 increased STAT6 phosphorylation in ␥␦17 cells. Furthermore, IL-4 signaling attenuated ␥␦17 cell production of IL-17A and IL-17F. IL-4 also decreased ␥␦17 cell expression of IL-23R as well as Sgk1. To determine whether STAT6 regulates ␥␦17 cell cytokine expression in vivo, we used a mouse model of Klebsiella pneumoniae lung infection in mice deficien...

show abstract

“…In fact, the presence of γδ T cells infiltrating the plaque in the brains of MS patients was reported; these cells were also found to be associated with high expression of heat shock proteins (Wucherpfennig et al, 1992). More recently, the greater presence of γδ T cells expressing CD161+high, CCR6+ was demonstrated in both the peripheral blood and CSF of MS patients in relapse (Schirmer et al, 2013). Interestingly, these cells were found to produce IL-17.…”

Section: Inflammation and Apoptosis At Peripheral Blood Level In Multmentioning

confidence: 97%

Role of inflammation and apoptosis in multiple sclerosis: Comparative analysis between the periphery and the central nervous system

Macchi

Marino-Merlo

Nocentini

et al. 2015

Journal of Neuroimmunology

View full text Add to dashboard Cite

Enriched CD161^highCCR6⁺γδ T Cells in the Cerebrospinal Fluid of Patients With Multiple Sclerosis

Cited by 68 publications

References 28 publications

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection

Role of inflammation and apoptosis in multiple sclerosis: Comparative analysis between the periphery and the central nervous system

Contact Info

Product

Resources

About

Enriched CD161highCCR6+γδ T Cells in the Cerebrospinal Fluid of Patients With Multiple Sclerosis

Cited by 68 publications

References 28 publications

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

IL-1β and IL-23 Promote Extrathymic Commitment of CD27+CD122− γδ T Cells to γδT17 Cells

STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection

Role of inflammation and apoptosis in multiple sclerosis: Comparative analysis between the periphery and the central nervous system

Contact Info

Product

Resources

About

Enriched CD161^highCCR6⁺γδ T Cells in the Cerebrospinal Fluid of Patients With Multiple Sclerosis