THU0039 DECIPHERING DISEASE-RELEVANT T CELL SUBSETS IN RHEUMATOID ARTHRITIS IDENTIFIES A NOVEL CELLULAR SUBSET OF PATHOGENETIC IMPORTANCE IN THERAPEUTIC RESISTANCE.
Authors: M. Nyirenda, I. Mcinnes, C. Goodyear
Journal: Annals of the Rheumatic Diseases (2020)

Background: Aberrant T cell responses are key in driving autoimmunity and are commonly associated with rheumatoid arthritis (RA). Unravelling pathways of importance in therapeutic partial response and failure is of critical importance, as this will potentially provide new insights into key drivers of immune-mediated pathogenesis. Objectives: To delineate disease-relevant T cell subsets in RA and assess their potential to act as cellular markers amenable to precision medicine approaches, particularly in the context of therapeutic partial or non-response. Methods: FACS-based immunophenotyping and ex-vivo functional response profiles of CD4 + CD161 + CCR2 + CCR5 + T cells were performed in peripheral blood mononuclear cells (PBMC) obtained from patients with RA and healthy controls, using previously characterised methodologies. RA patients fulfilled the 2010 ACR/EULAR criteria for RA. All samples were obtained after written consent, with the appropriate ethical approvals in place. Results: RA patients harboured a higher frequency of CCR2 + CCR5 + cells within the CD4 + CD161 + T cell compartment compared with healthy controls. In RA patients this T cell subset had a higher proportion of cells that secrete pro-inflammatory cytokines such as IL-17A, GM-CSF, IFN-γ, and TNF. Importantly, the CD4 + CD161 + CCR2 + CCR5 + T cell subset was significantly increased in DMARD non-responders compared to both responders and healthy controls. Moreover, in DMARD non-responders, these cells had a propensity to express increased proportions of pro-inflammatory cytokines. Notably, there was also a significant increase in the ratio of effector: regulatory T cell (Teff: Treg) compared to both responders and healthy controls. In addition, the CD4 + CD161 + CCR2 + CCR5 + T cell subset was less responsive to suppression by Tregs. In further support of a role for this T cell population in disease pathogenesis, the frequency of CD4 + CD161 + CCR2 + CCR5 + T cells significantly correlated with disease activity, as measured by the DAS28 (R 2 = 0.65; p = 0.003; n=11). Conclusion: Combined, our findings suggest that the CD4 + CD161 + CCR2 + CCR5 + T cell subset represents a substantially abnormal T cell subset in RA, exhibiting exaggerated pro-inflammatory responses, numerical abundance relative to Tregs, and resistant to regulation by Tregs. The CD4 + CD161 + CCR2 + CCR5 + T cell subset appears to be a marker of therapeutic response status in RA, via its contribution to disease pathology and highlights this subset as a potential therapeutic target in RA. References: [1]McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med . 2011;365(23):2205-19. [2]Mexhitaj I, Nyirenda MH, Li R, O’Mahony J, Rezk A, Rozenberg A, et al . Abnormal effector and regulatory T cell subsets in paediatric-onset multiple sclerosis. Brain . 2019;142(3):617-32. [3]Cosmi L, Cimaz R, Maggi L, Santarlasci V, Capone M, Borriello F, et al . Evidence of the transient nature of the Th17 phenotype of CD4 + CD161 + T cells in the synovial fluid of patients with juvenile idiopathic arthritis. Arthritis Rheum . 2011;63(8):2504-15. Disclosure of Interests: Mukanthu Nyirenda: None declared, Iain McInnes Grant/research support from: Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Janssen, and UCB, Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly and Company, Gilead, Janssen, Novartis, Pfizer, and UCB, Carl Goodyear: None declared