Anneli Peters

Induction and molecular signature of pathogenic TH17 cells

Interleukin 17 (IL-17)-producing helper T cells (TH17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that TH17 cells are main drivers of autoimmune tissue injury. However, not all TH17 cells are pathogenic; in fact, TH17 cells generated with transforming growth factor-β1 (TGF-β1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of TGF-β3 by developing TH17 cells was dependent on IL-23, which together with IL-6 induced very pathogenic TH17 cells. Moreover, TGF-β3-induced TH17 cells were functionally and molecularly distinct from TGF-β1-induced TH17 cells and had a molecular signature that defined pathogenic effector TH17 cells in autoimmune disease.

Th17 Cells Induce Ectopic Lymphoid Follicles in Central Nervous System Tissue Inflammation

Ectopic lymphoid follicles are hallmarks of chronic autoimmune inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis, Sjögrens syndrome, and myasthenia gravis. However, the effector cells and mechanisms that induce their development are unknown. Here we showed that in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, Th17 cells specifically induced ectopic lymphoid follicles in the central nervous system (CNS). Development of ectopic lymphoid follicles was partly dependent on the cytokine interleukin 17 (IL-17) and on the cell surface molecule Podoplanin (Pdp), which was expressed on Th17 cells, but not on other effector T cell subsets. Pdp was also crucial for the development of secondary lymphoid structures: Pdp-deficient mice lacked peripheral lymph nodes and had a defect in forming normal lymphoid follicles and germinal centers in spleen and lymph node remnants. Thus, Th17 cells are uniquely endowed to induce tissue inflammation, characterized by ectopic lymphoid follicles within the target organ.

The many faces of Th17 cells

Th17 cells have been shown to be strong inducers of tissue inflammation and autoimmune diseases. However, not all Th17 cells are pathogenic and increasing data suggest that Th17 cells may come in different flavors. Thus, Th17 cells cannot be described using a narrow schematic, but instead Th17 cells comprise a wide spectrum with a range of effector phenotypes. Here, we review the key factors that generate such diversity, as well as the cytokines and transcription factors that are differentially expressed in pathogenic and nonpathogenic Th17 cells. This new knowledge can be used to identify molecules that make Th17 cells pathogenic and determine how these cells could be targeted to suppress autoimmune diseases.

Podoplanin-Rich Stromal Networks Induce Dendritic Cell Motility via Activation of the C-type Lectin Receptor CLEC-2

Summary To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.

Immune checkpoints in central nervous system autoimmunity.

Summary:  A number of autoimmune diseases, including multiple sclerosis, are mediated by self‐reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms, including regulation through coinhibitory receptors and suppression by regulatory T cells. However, if these mechanisms fail, self‐reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA‐4 (cytotoxic T‐lymphocyte antigen‐4), PD‐1 (programed death‐1), Tim‐3 (T‐cell immunoglobulin‐ and mucin domain‐containing molecule 3), and TIGIT (T‐cell immunoreceptor with immunoglobulin and ITIM domains) act at different checkpoints to inhibit autoreactive T cells and suppress the development of central nervous system autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non‐redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. Therefore, we propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity.

IL-27 Induces Th17 Differentiation in the Absence of STAT1 Signaling

It is known that differentiation of Th17 cells is promoted by activation of STAT3 and inhibited by activation of STAT1. Although both transcription factors are activated by several cytokines, including IL-6, IL-21, and IL-27, each of these cytokines has a very different effect on Th17 differentiation, ranging from strong induction (IL-6) to strong inhibition (IL-27). To determine the molecular basis for these differences, we measured STAT3 and STAT1 activation profiles for IL-6, IL-21, and IL-27, as well as for cytokine pairs over time. We found that the ratio of activated STAT3/activated STAT1 is crucial in determining whether cytokines promote or inhibit Th17 differentiation. IL-6 and IL-21 induced p-STAT3/p-STAT1 ratios > 1, leading to the promotion of Th17 differentiation, whereas IL-27 or IL-6+IL-27 induced p-STAT3/p-STAT1 ratios < 1, resulting in inhibition of Th17 differentiation. Consistent with these findings, we show that IL-27 induces sufficient p-STAT3 to promote Th17 differentiation in the absence of STAT1. Furthermore, IL-27–induced STAT1-deficient T cells were indistinguishable from bona fide highly proinflammatory Th17 cells because they induced severe experimental autoimmune encephalomyelitis upon adoptive transfer. Our results suggest that the ratio of p-STAT3/p-STAT1 induced by a cytokine or cytokine pairs can be used to predict whether they induce a competent Th17-differentiation program.

Podoplanin negatively regulates CD4+ effector T cell responses.

Podoplanin (PDPN, also known as Gp38) is highly expressed on the surface of lymphatic endothelial cells, where it regulates development of lymphatic vessels. We have recently observed that PDPN is also expressed on effector T cells that infiltrate target tissues during autoimmune inflammation; however, the function of PDPN in T cells is largely unclear. Here, we demonstrated that global deletion of Pdpn results in exaggerated T cell responses and spontaneous experimental autoimmune encephalomyelitis (EAE) in mice with a susceptible genetic background. In contrast, T cell-specific overexpression of PDPN resulted in profound defects in IL-7-mediated T cell expansion and survival. Consequently, these animals exhibited a more rapid resolution of CNS inflammation, characterized by a reduced effector CD4+ T cell population in the CNS. Mice harboring a T cell-specific deletion of Pdpn developed exacerbated EAE, with increased accumulation of effector CD4+ T cells in the CNS. Transcriptional profiling of naturally occurring PDPN+ effector T cells in the CNS revealed increased expression of other inhibitory receptors, such as Pd1 and Tim3, and decreased expression of prosurvival factors, including Il7ra. Together, our data suggest that PDPN functions as an inhibitory molecule on T cells, thereby promoting tissue tolerance by limiting long-term survival and maintenance of CD4+ effector T cells in target organs.

Immune Checkpoints in CNS Autoimmunity

Summary:  A number of autoimmune diseases, including multiple sclerosis, are mediated by self‐reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms, including regulation through coinhibitory receptors and suppression by regulatory T cells. However, if these mechanisms fail, self‐reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA‐4 (cytotoxic T‐lymphocyte antigen‐4), PD‐1 (programed death‐1), Tim‐3 (T‐cell immunoglobulin‐ and mucin domain‐containing molecule 3), and TIGIT (T‐cell immunoreceptor with immunoglobulin and ITIM domains) act at different checkpoints to inhibit autoreactive T cells and suppress the development of central nervous system autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non‐redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. Therefore, we propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity.

Th17 and Th22 Cells

Th17 cells are a subset of effector CD4 T cells that induce neutrophilic tissue inflammation, particularly in mucosal tissues. While they play a critical role in host defense against extracellular bacteria and fungi, they also have been implicated in the pathogenesis of a number of T cell–mediated autoimmune disorders, including multiple sclerosis, rheumatoid arthritis, and psoriasis. Consistent with their dichotomous roles in promoting host defense and inducing autoimmunity, several subtypes of Th17 cells have been described with distinct effector functions and differing ability to induce autoimmune tissue inflammation. Moreover, Th17 cells are markedly plastic, both in their expression of cytokines typically associated with other effector T cell subsets and in their relationship with regulatory CD4 T cells; and this plasticity has important functional consequences. In this article, we describe the mechanisms that control Th17 cell differentiation, function, and plasticity, as well as highlight Th22 cells, a recently described and closely related CD4 T cell subset.

Immune checkpoints in central nervous system autoimmunity: Inhibitory receptors in CNS autoimmunity

Summary:  A number of autoimmune diseases, including multiple sclerosis, are mediated by self‐reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms, including regulation through coinhibitory receptors and suppression by regulatory T cells. However, if these mechanisms fail, self‐reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA‐4 (cytotoxic T‐lymphocyte antigen‐4), PD‐1 (programed death‐1), Tim‐3 (T‐cell immunoglobulin‐ and mucin domain‐containing molecule 3), and TIGIT (T‐cell immunoreceptor with immunoglobulin and ITIM domains) act at different checkpoints to inhibit autoreactive T cells and suppress the development of central nervous system autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non‐redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. Therefore, we propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity.