Immune 'hubs' in the joint: source of cells that support inflammation in rheumatoid arthritis found

Mini “communication hubs” of the immune system, tertiary lymphoid structures (TLS), have been discovered in the joints of people with rheumatoid arthritis (RA), where the same population of T cells actually “self-reproduces” and supplies the inflammation with fresh attack units. Researchers from Kyoto University have shown that the so-called peripheral T-helpers (Tph) exist in two states: stem-like Tph live inside the TLS, communicate with B cells and produce offspring; some of them are “released” to the outside as effector Tph, which then keep the inflammation fire burning in the tissue. This may explain why inflammation persists in some patients despite therapy.

Background

Rheumatoid arthritis (RA) is a chronic autoimmune inflammation of the synovial membrane of the joints. Even with modern targeted drugs (anti-TNF, anti-IL-6, JAK inhibitors, B-cell strategies), some patients still have "smoldering" local inflammation, erosions and pain. This suggests that the tissue has mechanisms for self-sustaining the immune response, which are not always suppressed by systemic therapy.

One of these mechanisms is considered to be tertiary lymphoid structures (TLS) - "temporary lymph nodes" right in the synovium. Inside the TLS, T- and B-cells, dendritic cells, follicular structures coexist; antigen presentation, B-cell maturation and autoantibody production occur there. It is in such "communication nodes" that rare but influential T-cell populations can live and renew themselves.

In recent years, attention has shifted to peripheral T-helpers (Tph) - CD4⁺ cells that, unlike classic follicular Tfh, operate outside the follicles but powerfully assist B-cells and fuel the autoantibody response. They have been found in the synovium of RA and linked to disease activity, but key questions remain: do Tph have subpopulations with different roles, where exactly in the tissue are they localized, how do they interact with B-cells, and what maintains their “conveyor belt”?

Answers to such questions have become possible thanks to single-cell technologies (scRNA-seq) and spatial transcriptomics, which allow us to simultaneously determine the cell’s “passport” (which genes it expresses) and its tissue coordinates (who it is adjacent to and what signals it receives). This is especially important for RA: the disease is a network phenomenon, and it can only be understood by linking cell types with their microniche.

It is in this context that it is relevant to find out whether Tph has a hierarchy of states - from the "trunk-like" reserve in TLS to the "effector front" in tissue - and whether it is possible to hit the source of persistent inflammation with therapy, rather than the consequences (cytokines at the output): the niche where Tph are renewed and train B-cells. Such "targeted" logic would open the way to more precise stratification of patients (by the presence/activity of TLS and Tph subsets) and to new combined treatment strategies that turn off the inflammation "factory" and not just extinguish its products.

How scientists saw it

The team analyzed tissue from inflamed joints and blood from RA patients using a “multi-omic” approach: single-cell RNA sequencing, spatial transcriptomics (where exactly in the tissue the cells are located and who they are next to) and functional co-cultures of T and B cells. This profile allows not only to describe the cell types, but also to reconstruct the scenario of their interactions inside the joint. The results are published in Science Immunology.

• Two faces of Tph:
  • Stem-like Tph - slowly dividing "reservoirs" with a sign of self-renewal, localized inside the TLS and tightly contacted with B-cells.
  • Effector Tph - more "incendiary" cells, go outside the TLS, where they interact with macrophages and cytotoxic T-cells, fueling inflammation.
• Where the source lives: Spatial transcriptomics has shown that it is in the TLS that stem-like Tph are concentrated, and in laboratory co-cultures with B-cells they mature into effector Tph, simultaneously activating the B-cells themselves.
• Why this is important: The constant “recharge” of effector Tph from the trunk-like pool explains the persistence of inflammation even under treatment and outlines a new point of intervention - a blow to the source, not to the consequences.

What does this change for understanding RA today?

Rheumatoid arthritis is a disease of a network, not a single cell. In recent years, the focus has been on a rare but influential population of Tph (PD-1^hi, more often CXCR5^-), which was previously caught in the synovium and associated with B-cell activation and antibody production. The new work adds an important twist: not all Tph are equal, and it is the stem-like Tph in the “hubs” that may be the root of the problem in some patients.

• Clinical logic:
  • if the TLS niche for stem-like Tph is switched off or “de-energized”, the flow of effector Tph will dry up - it will be more difficult for inflammation to persist;
  • markers reflecting the presence/activity of TLS and stem-like Tph can become indicators of prognosis and response to therapy;
  • this explains the phenomenon of incomplete remission, when systemic biomarkers and symptoms improve, and focal activity in the joint “smolder”.

Key Results

• There are "immune hubs" in the joint. These are not lymph nodes, but temporary lymphoid structures right in the inflamed tissue, where cells learn and multiply. That's where the Tph "reservoir" sits.
• There is a "factory" and a "front." Inside the hubs is the "factory" of stem-like Tph+ B cells; outside is the "front," where effector Tphs coordinate inflammatory partnerships with macrophages and killer T cells.
• This dichotomy is the reason for the persistence of inflammation. As long as the factory is alive, the front will not be left without reinforcements. This means that therapy "at the place of origin" may be more effective.

What this might mean for treatment

Today's arsenal for RA is powerful: TNF blockers, IL-6, JAK inhibitors, B-cell strategies. But in 30% of patients the response remains unsatisfactory - probably because TLS and stem-like Tph restart the cascade. New data suggest directions for development:

• Point targets in the niche:
  • signals that keep T and B cells in the TLS;
  • factors for the self-renewal of stem-like Tph;
  • “Tph↔B-cell” axes that trigger differentiation into effector Tph.
• Diagnostics and stratification:
  • visualization/histology of TLS in synovium as a biomarker of “poor response”;
  • single-cell and spatial panels for monitoring Tph states in biopsies;
  • combination of circulating Tph with clinical features to select a line of therapy.
• Combinations with current drugs: Suppressing the Tph “factory” may enhance the effects of existing drugs, reducing the need for escalation. (This direction requires clinical trials.)

Context: Where did Tph come from and why is there so much attention around it?

The idea that in addition to follicular Tfh there are “extrafollicular” B-cell helpers took shape in the 2010s, when CXCL13-producing CD4 cells without classic Tfh markers were found in the synovium of RA. They were called peripheral helper T cells - Tph. Today, Tph is associated with disease activity, seropositivity, and synovitis severity, and “neighboring” phenotypes are found in the lungs and other tissues in RA. The new work actually adds a hierarchy within Tph and ties it to a specific microlocation - TLS.

Important Disclaimers

• This is a study of human tissues and laboratory co-cultures; the causality and "therapeuticity" of the targets has yet to be proven in the clinic;
• TLS are heterogeneous: in some scenarios they are associated with a response to therapy, in others - with its absence; fine stratification is needed;
• Single-cell and spatial methods are still limited in availability, but are rapidly becoming cheaper and moving towards clinical centers.

What's next?

• To test whether the stem-like Tph pool changes in response to different drug classes and whether it predicts therapy outcome;
• Develop “TLS-targeted” interventions – from molecular inhibitors to local delivery to the synovium;
• Create accessible tests (Tph/TLS marker panels) for routine rheumatology - so that the selection of “candidates for a new strategy” does not have to wait for years.

Source: Masuo Y. et al. Stem-like and effector peripheral helper T cells comprise distinct subsets in rheumatoid arthritis. Science Immunology, August 15, 2025. DOI: 10.1126/sciimmunol.adt3955