Changing behind the scenes

Periodontitis is triggered by outgrowth of oral microbiota with resulting enhanced inflammatory response that leads to local damage, eventually causing tooth loss. Chronic periodontitis is also associated with increased incidence and morbidity of systemic autoimmune and inflammatory diseases and thus represents a serious health risk. Although rare, studies in humans with severe periodontitis due to genetic inborn errors of immunity that prevent neutrophil migration into tissues strongly support the role of dysbiosis and over-production of IL-17 as underlying mechanisms driving chronic gum inflammation (Gaffen and Moutsopoulos, 2020). Early clinical case studies suggest controlling IL-17 is an effective therapy, supporting development of clinical trials. In contrast, people with genetic deficiencies that reduce Th17 cells or IL-17 signaling have lower periodontitis rates, and IL-17 blockade for autoimmune disease increases risk for oral candidiasis but not periodontitis (Gaffen and Moutsopoulos, 2020). These clinical observations and mouse models support a dominant pathogenic role for Th17 cells and IL-17 in periodontitis.

The study by McClure et al. (2024) set out to investigate plasticity of Th17 cells in a mouse model of periodontitis induced by placement of a ligature around premolars; aptly named ligature-induced periodontitis (LIP) is driven by the ligature-provided platform for outgrowth of commensal bacteria at the tooth–gum interface, triggering periodontal inflammation. Th17 cells come in different “flavors,” with varying compositions of cytokines produced in addition to IL-17 that are thought to determine pro-inflammatory versus non-pathogenic status of Th17 cells. Studies using IL17cre fate-tracker mice, in which cre-mediated expression of a fluorophore marks cells that once produced IL-17, have revealed the high degree of functional plasticity exhibited by Th17 cells (Mills, 2023). For example, in the mouse model of multiple sclerosis, a high proportion of Th17 cells convert towards a Th1 or Th17/Th1 phenotype that is considered more pathogenic and resembles mixed populations of Th17 and Th1 cells found in human sites of autoimmune tissue inflammation (Hirota et al., 2011). Understanding Th17 plasticity is clinically important, since it would be ideal to spare the beneficial functions of barrier-resident Th17 cells that regulate microbiota, mycobiome, and fungal pathogens from the undesirable Th17 cells involved in driving inflammatory disease.

Unexpectedly, McClure et al. (2024) found that Th17 cells in inflamed gingiva demonstrate little accumulation of effector cytokines beyond IL-17. This is surprising based on the multitude of studies showing a high degree of Th17 plasticity in inflamed tissues, particularly under chronic inflammatory scenarios as develop in periodontitis (Mills, 2023). It is also surprising in light of a recent study showing that IL-23 can be produced by inflamed gum epithelia in mouse and human periodontitis, since IL-23 is a known driver of pathogenic converted Th17 effector cells in other models (Kim et al., 2024). The finding of low Th17 plasticity in gingiva is reminiscent of Th17 cells in the small intestine that are induced by the murine commensal segmented filamentous bacteria (SFB); SFB-specific Th17 cells also show relatively low metabolic activity corresponding to lack of overt inflammation while regulating SFB levels (Omenetti et al., 2019). However, if intestinal epithelia cannot respond to IL-17, then SFB outgrowth results in enhanced numbers of IL-17–producing cells in a frustrated feedback loop (Kumar et al., 2016), similar to what may be occurring in periodontitis when microbiota outgrowth is not brought under control.

Intriguingly, Th17 plasticity was observed in the draining LN, but with a beneficial outcome for oral health (McClure et al., 2024). About a third of Il17cre-marked Th17 cells converted to a T follicular helper (TfH) phenotype with high expression of TfH transcription factor Bcl6 and surface markers CXCR5 and PD1, reduced expression of the Th17 transcription factor RORγt and production of IL-17, and loss of Th17 tissue homing receptor CCR6. These exTh17-TfH cells represent a very small fraction of total TfH and could be easily missed without the use of the fate-tracker tool. In a key experiment, McClure et al. (2024) deleted Bcl6 expression only in Th17-lineage cells. Induction of LIP in Il17^cre-Bcl6^fl/fl mice did not affect conventional TfH cell numbers but revealed that the small fraction of exTh17-TfH cells plays a significant role in promoting protective IgG1 and IgG2c that reduces IL-17, neutrophil recruitment, and periodontal inflammation during LIP. Since blocking Th17 to TfH conversion results in increased amounts of bacterial species in similar proportions, the authors surmise that it is the biomass of the oral microbiota that sets the magnitude of the corresponding Th17-driven inflammatory response. Hence, the threshold for inflammatory disease would be based on numbers of IL-17–producing cells rather than conversion of the Th17 phenotype, since Th17 cells are already present in gingiva under homeostasis.

What makes this small population of exTh17-TfH cells “special” amongst the larger conventional TfH population induced by LIP? The study does not fully address this but offers some clues. Converted exTh17-TfH cells also had higher expression of Bcl6 compared to conventional TfH cells, suggesting possible enhanced function. IL-17 has been linked to promoting antibody production through various mechanisms including TfH migration and LN stromal cell activation (Majumder and McGeachy, 2021). One could speculate that the positioning of TfH cells with residual IL-17 production in relation to B cell follicles could increase their potency through local stromal activation. Another possibility is that the antigen specificity of Th17 cells, possibly pre-existing under homeostatic conditions, favors antigen-driven conversion of relevant TfH cells under dysbiotic conditions. Antigen specificity and T cell receptor usage were not investigated, but along with deep sequencing could give future clues to what makes this small population of exTh17-TfH cells critical amongst their peers for microbiota control.

LN draining sites of chronic T cell activation, namely tumors and autoimmune target organs, have been found to harbor reservoirs of stem-like T cells that generate short-lived tissue effectors (Gearty et al., 2022). In this regard, one could consider that LN draining oral cavity tissues may harbor commensal-specific Th17 cells that are more amenable to conversion than peripheral tissue counterparts. Th17 to TfH plasticity supports microbiota-driven IgA production in Peyer’s patches of naïve mice living in specific pathogen–free conditions (Hirota et al., 2013). To test whether Th17 to TfH conversion is present in draining LN during other inflammatory conditions, McClure et al. (2024) used fate-tracker mice to follow plasticity of LN Th17 cells in mouse models of psoriasis, gut infection, and arthritis, and found no evidence for a Th17 to TfH switch. This result supports context-dependent drivers of Th17 plasticity, that could be related to target antigens (commensal microbes versus de novo inflammatory stimuli) or the LN environment induced by different immune activators. They identified IL-6 as a key driver of Th17 to TfH conversion in LIP, but since IL-6 is commonly present in inflammation, there must be additional factors regulating this process in the periodontitis model.

This study reinforces the complex interplay between microbiota and immunity at barrier surfaces and extending to their associated secondary lymphoid organs. Loss of microbial control triggers amplification of homeostatic mechanisms leading to a type of frustrated bystander immunopathology, supporting therapeutic use of IL-17 blockade to quell inflammation. However, it is becoming clear that Th17 cells are also playing important beneficial roles almost “behind the scenes” in promoting protective B cell responses that help limit inflammation. In the LIP model, generation of a low frequency but apparently high potency Th17-TfH cell drives IgG1 and IgG2c that aid control of dysbiosis, acting as negative feedback to reduce activation of Th17-mediated pathology. In models of gut inflammation, IL-17 signaling in LN can promote the generation of protective B cells that produce IL-10 along with increased antibody to control infection and limit Th17 pathology (Wu et al., 2021). It is, however, worth noting that B cells have also been proposed as drivers of pathology in periodontitis, and increased circulating Th17-like TfH cells have been described in humans with autoimmune disease (Iwamoto and Ueno, 2022), suggesting that generation of autoreactive exTh17-TfH cells could instead promote chronic inflammation. Hence, more work is needed to dissect beneficial and protective B cell activation in relation to Th17-TfH cells and disease context. Clinical trials have revealed a similar dichotomy for IL-17 blockade, finding life-changing efficacy for many people with psoriasis while failing and sometimes causing exacerbations in people with inflammatory bowel disease likely due to important roles for IL-17 in wound repair and microbiota control. A small number of patients with severe periodontitis due to inborn errors of immunity have been treated with IL-17 blockade with remarkable efficacy (Gaffen and Moutsopoulos, 2020). One question that could be addressed in these ongoing clinical studies is whether the oral IgG response is altered by IL-17 blockade. Extending beyond chronic inflammatory disease, this study and others showing roles for Th17 cells in promoting protective antibody raise the idea that designing vaccine adjuvants that enhance these beneficial Th17 and exTh17-TfH populations could improve their efficacy.