No abstract

Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritisMaurice, M.M.; Lankester, A.C.; Bezemer, A.C.; Geertsma, M.F.; Tak, P.P.; Breedveld, F.C.; van Lier, R.A.W.; Verweij, C.L.

In rheumatoid arthritis (RA), T cells isolated from the synovial fluid (SF) show impaired responses to mitogenic stimulation compared with T cells from the peripheral blood (PB). Here it is reported that hyporesponsiveness of SF T cells correlated with a significant decrease in the levels of the intracellular redox-regulating agent glutathione (GSH). GSH was decreased in both CD4+ (p = 0.0022) and CD8+ (p = 0.0010) SF T cell subsets compared with PB CD4+ and CD8+ T cells in RA patients. Levels of thioredoxin (TRX), another key redox mediator, previously found to be secreted under conditions of oxidative stress, were found to be significantly increased in SF compared with plasma samples of RA patients (p = 0.005). Increased levels of TRX in the SF of inflamed joints was found to be associated with RA when compared with other arthritides (p = 0.007). Restoration of GSH levels in SF T cells with N-acetyl-L-cysteine (NAC), enhanced mitogenic induced proliferative responses and IL-2 production. Collectively, these data impute an important role to an altered redox state in the hyporesponsiveness of joint T cells in patients with RA.

CD27, a member of the TNFR family, is expressed on most but not all peripheral blood CD4+ T cells. The small fraction of CD4+ T cells with a CD27- phenotype exclusively reside within the CD45RA-CD45RO+ subset. We previously provided evidence that CD27- cells are functionally differentiated cells that have lost CD27 expression as a result of persistent antigenic stimulation. We here show that compared with CD4+CD45RA-CD27+ cells, CD4+CD45RA-CD27- lymphocytes have a high expression of the beta 1 integrins VLA-4 and -5 and of the beta 2 integrin CD11b. Molecules implicated in homing of T cells to peripheral lymphnodes like CD31 and CD62L (L-selectin) are poorly expressed on CD27- cells, whereas receptors involved in organ-specific homing, e.g., cutaneous lymphocyte Ag and HML-1 (alpha E beta 7), are present on CD27- rather than CD27+ T lymphocytes. CD27+ and CD27- cells do not differ notably in the expression of activation molecules such as CD25, CD38, and CD70 (CD27 ligand) but CD7 is markedly absent on approximately half of the CD27- cells. Analysis of mutations in the HPRT gene, as measurement for the amount of cell divisions that have occurred in particular T cell populations in vivo, showed that CD45R0+ cells have a 2 to 5 times higher mutant frequency than CD45RA+ cells, whereas CD45R0+CD27- cells do not differ in this respect from CD45R0+CD27+ cells. In line with this latter finding, cells in G2M phase can only be found in the transitional, CD45RAbrightCD45R0bright subset but not in CD45R0+, CD45RA-, or CD27- cells. Our results imply that the CD27- population contains tissue-specific, specialized "primed" T cells that evolve in vivo independently from extensive cellular division.

Accessory molecules on T cells can support adhesion and transduce agonistic signals that facilitate Ag receptor-induced T cell activation. The T cell differentiation Ag CD2 may exert both functions, as has been amply demonstrated in studies with CD2 mAbs. In addition, experiments in which either purified ligand (CD58) or transfected CD2 and CD58 molecules were used have confirmed this notion. However, controversy exists as to whether CD2 alters its affinity for CD58 in the course of T cell stimulation, and whether this putative affinity change affects CD2-mediated activation signals. We now describe a CD2 mAb (HIK27) that recognizes an epitope constitutively expressed on resting T cells and induces increased adhesiveness of CD2 toward CD58. Addition of HIK27 to a stimulatory but nonmitogenic pair of CD2 mAbs induces a strong proliferative response. Finally, HIK27 was found to be co-mitogenic with CD58 expressed on sheep erythrocytes, B cell lines, and CD58-transfected L cells. The simultaneous modulation of CD2 adhesion and signaling on HIK27 binding suggests that both functions of the molecule may be enhanced in the course of T cell stimulation.