The bias for Th1 cell differentiation of rheumatoid arthritis T cells is characteristic of memory but not of naive T cells

An impaired ability of CD4 memory T cells to differentiate into immunomodulatory Th2 cells has been documented in patients with rheumatoid arthritis (RA) and has been implicated in the initiation and perpetuation of the characteristic Th1 dominated rheumatoid inflammation. To determine the stage of T-cell maturation at which the bias for Th1 cell differentiation becomes manifest, we investigated Th cell differentiation from resting CD4 CD45RA (naive) and CD45RO (memory) T cells in patients with untreated early RA (mean disease duration <8 months) and in age- and sex-matched healthy controls in vitro. No differences in the cytokine secretion profile, as assessed by flow cytometry, between patients and control subjects were detected in freshly isolated naive or in freshly isolated memory T cells. Th2 cells could be induced from naive T cells in all healthy donors and in all RA patients by priming with monoclonal antibodies (mAbs) to CD3 and CD28. Exogenous IL-4 was not required for Th2 differentiation from naive cells and did not consistently increase Th2 priming efficacy. In contrast to naive cells, Th2 effectors were effectively generated from memory T cells by stimulation with anti-CD28 without ligation of the T-cell recceptor. This mode of stimulation generated Th2 cells from memory T cells of all healthy controls but in only one third of the RA patients. The data suggest that CD4 memory T cells from the majority of patients with early RA manifest a deficiency in their capacity to differentiate into Th2 effectors. In contrast, naive T cells are capable of differentiating into Th2 cells with appropriate stimulation suggesting that the bias in Th1 differentiation of most RA patients may be acquired during T-cell maturation presumably in response to antigenic stimulation.