Background/Purpose: the T-cell memory compartment is multi-faceted and encompasses multiple subsets with divergent properties. In addition to central memory (T_CM) and effector memory (T_EM) cells, the spectrum of immunological memory has been recently extended with the identification of memory stem T cells (T_SCM). Gene expression profiling, corroborated by in vitro and in vivo experimental results, posits T_SCM upstream T_CM and T_EM in T-cell ontology (Gattinoni, Nat Med 2011; Cieri, Blood 2013). While self-renewing T_SCM 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, T_SCM may represent a reservoir of long-lived T cells with undesired and detrimental specificities responsible for disease perpetuation. 

Methods: we characterized T_SCM 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 T_SCM 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 T_SCM expansion correlated with disease severity (quantified by DAS28 score), suggesting an active role of T_SCM in disease pathophysiology. Functionally, expanded CD4⁺ T_SCM displayed a preferential T_H17 polarization, known to have a fundamental pathogenic role in rheumatic synovitis, and thus further corroborating T_SCM 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 T_SCM and restored T-cell homeostasis in responder patients. Prior to etanercept treatment, T_SCM 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 T_SCM lymphocytes in the context of RA. Finally, ongoing experiments will elucidate whether T_SCM accumulation is due to the selective expansion of arthritogenic clones through the characterization of the TCR repertoire and antigen-specificities of T_SCM cells from RA patients. 

Conclusion: understanding the dynamic and quantitative aspects of T_SCM lymphocyte behavior in RA will have profound implications for devising strategies to counteract T-cell dysfunction in RA patients.

---

« Back to 2014 ACR/ARHP Annual Meeting

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/