Session Title: T cell Biology in Rheumatoid Arthritis and Other Arthritis
Session Type: Abstract Submissions (ACR)
Background/Purpose: the T-cell memory compartment is multi-faceted and encompasses multiple subsets with divergent properties. In addition to central memory (TCM) and effector memory (TEM) cells, the spectrum of immunological memory has been recently extended with the identification of memory stem T cells (TSCM). Gene expression profiling, corroborated by in vitro and in vivo experimental results, posits TSCM upstream TCM and TEM in T-cell ontology (Gattinoni, Nat Med 2011; Cieri, Blood 2013). While self-renewing TSCM would be highly desirable if bearing protective specificities, this very same cell subpopulation may also represent a foe when considering T-cell mediated pathologies. We hypothesized that, in these clinically relevant contexts, TSCM may represent a reservoir of long-lived T cells with undesired and detrimental specificities responsible for disease perpetuation.
Methods: we characterized TSCM dynamics in 15 patients with active rheumatoid arthritis (RA) and upon treatment with etanercept (median time from anti-TNF treatment onset: 3 months). T-cell subset composition and function was evaluated by 11-colors multiparametric flow cytometry.
Results: we found that TSCM cells, defined as CD45RA+CD62L+CD95+, are significantly more represented in terms of frequencies and absolute counts in patients with active RA as compared to age- and sex-matched healthy controls. Of notice, the extent of TSCM expansion correlated with disease severity (quantified by DAS28 score), suggesting an active role of TSCM in disease pathophysiology. Functionally, expanded CD4+ TSCM displayed a preferential TH17 polarization, known to have a fundamental pathogenic role in rheumatic synovitis, and thus further corroborating TSCM lymphocytes as a potential novel player in RA pathogenesis and perpetuation. Importantly, TNF-a neutralization, upon etanercept administration, efficiently reduced the frequency and number of circulating TSCM and restored T-cell homeostasis in responder patients. Prior to etanercept treatment, TSCM lymphocytes expressed TNFR2 to significantly higher levels compared to the other T-cell subsets both in CD4+ and CD8+ compartments, suggesting that TNF-a might act as a costimulatory signal for TSCM lymphocytes in the context of RA. Finally, ongoing experiments will elucidate whether TSCM accumulation is due to the selective expansion of arthritogenic clones through the characterization of the TCR repertoire and antigen-specificities of TSCM cells from RA patients.
Conclusion: understanding the dynamic and quantitative aspects of TSCM lymphocyte behavior in RA will have profound implications for devising strategies to counteract T-cell dysfunction in RA patients.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/memory-stem-t-cells-are-selectively-enriched-in-patients-with-rheumatoid-arthritis-contract-upon-anti-tnf-treatment-and-may-provide-a-long-term-reservoir-of-arthritogenic-lymphocytes/