gms | German Medical Science

Background: Patients with rheumatic disorders such as rheumatoid arthritis (RA) or spondyloarthritis (SpA) suffer from increased incidence and enhanced severity of infectious diseases. This enhanced vulnerability is conferred either by the primary disease and/or the immunomodulatory treatment. Since CD4⁺ T cells orchestrate immunity against infections, we hypothesized that CD4⁺ T cells were dysfunctional in patients with rheumatic diseases.

Methods: We studied the activation status and the reactivityupon anti-CD3/anti-CD28 stimulationof CD4⁺ T cells from patients with RA, SpA, and of healthy controls via FACS-based methods. Patient groups were analyzed for treatment either withithtumor necrosis factor-α (TNF-α)-blocking agents or abatacept (RA: n=38, SpA: n=30, control: n=30).

Results: The analysis of patient derived CD4⁺ T cells revealed an enhanced basal activation status as indicated by augmented spontaneous proliferation and increased expression of inducible T cell costimulator (ICOS) and the exhaustion marker programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Upon stimulation, patient derived CD4⁺ T cells showed significantly reduced IL-2 responses, impaired proliferation, and enhanced activation induced cell death (AICD). These data indicated a dysfunctional T cell compartment in terms of CD4⁺ T cell exhaustion. Intriguingly, RA patients treated with the second-signal CTLA-4 inhibitor abatacept carried CD4⁺ T cells that were less exhausted than CD4⁺ T cells from otherwise treated patients. This observation is further supported by the previously published clinical observation that abatacept-treated RA patients suffer less frequently from infections compared with RA patients treated differently. Similarly, anti-PD-1 treatment increased IL-2 expression of T cells from several RA and SpA patients in in vitro stimulation experiments.

Conclusion: In conclusion these results indicate that T cells from RA and SpA patients show different levels of exhaustion, which can at least partially be reverted by treatment with checkpoint inhibitors. These observations highlight the need to specifically consider individualized treatments of patients with rheumatic disorders aiming at readjusting the balance between immunosuppression and auto-inflammation.