Phenotypic analysis of CD26+ peripheral blood monocytes and dendritic cells in rheumatoid arthritis patients under immunomodulatory therapies

Myeloid lineage-derived cells are key orchestrators of immune function and contribute to several chronic inflammatory disorders, such as rheumatoid arthritis (RA). The landscape of how these detrimental pro-inflammatory roles evolve over the course of the disease and the impact of therapies on them is being unraveled by recent immune-cell profiling studies. An alternative phenotyping using CD4 and CD45R0 expression to assess monocyte (Mo) and DC subsets allowed us to re-evaluate CD26 expression, an antigen with key migratory functions via its dipeptidyl peptidase (DPP4) activity on chemokines, in myeloid cells. Myeloid DCs barely express CD26 (while plasmacytoid pDCs do), and the intermediate Mo (intMo) subset is enriched in CD26. In a cohort of RA patients under treatment, together with the known expansion of Mo and the impairment of DC subsets and intMo, the CD26 expression was reduced, except for the intMo subset, enriched in CD26. The CD26 expression levels correlated with disease activity (DAS28 and its components), with therapy-specific patterns. Treatment with classical or biologic DMARDs, anti-IL6R, CTLA4-Ig, anti-TNF and anti-CD20, differentially modulated Mo subsets, the latter two reducing classical monocytes (cMo) while anti-TNF modestly increasing pDCs frequencies. Only anti-IL6R therapy increased total intMo % while decreasing the CD26+ intMo % (anti-CD20 also decreased the latter; on the contrary, CTLA4-Ig and anti-TNF increased it). Therapies variably restored CD26 density, except for anti-IL6R and anti-CD20. In conclusion, given that DPP4 inhibitors have shown contradictory effects in RA, their specific impact on these CD26+ APC functions warrants further investigation. Furthermore, the strong both positive and negative correlations found between soluble sCD26 levels and CD26+ frequencies (most strongly with pDCs) might support a sCD26 secretion independent of membrane-bound CD26, and CD26+ cell frequency associations with levels of anti-CD26 autoantibodies might suggest Ag-Ab complexes involvement on CD26 expression only in certain contexts.