Background/Purpose:

Regulatory T cells (Treg) are impaired in human Systemic Lupus Erythematosus (SLE) and contribute to T cell activation. However, the mechanisms responsible for the Treg deficiency in SLE remain unclear. Our group recently reported that OX40L was expressed by myeloid APCs in blood and in inflamed tissues of SLE patients. OX40L stimulation induced human CD4+ T cells to express TFH associated molecules, and was sufficient to induce memory and naïve CD4+ T cells to become functional B cell helpers.

OX40L has been also shown to block Treg functions both in mice and in humans. We hypothesized that OX40L/OX40 axis was implicated in Treg and regulatory follicular helper T cell (TFR) dysfunction in human SLE.

Methods: Flow cytometry was used for analysis of cell surface and intracellular molecules expressed on blood cells of SLE patients (n = 61) and healthy donors (HD)(n = 16). Using recombinant sOX40L, in vitro-generated SLE-DCs expressing OX40L, and DCs from patients, the impact of OX40/OX40L axis on the function of cTregs (CD4+CXCR5-CD25high Foxp3+) and TFR (CD4+CXCR5+CD25high Foxp3+) purified from HD was studied in co-culture experiments.

Results:

OX40L/OX40 axis engagement on Tregs and TFR not only specifically impaired their ability to regulate T effector cells proliferation but also their ability to suppress TFH-dependent B cell activation, and immunoglobulin secretion. Indeed, we observed that soluble and membrane-bound OX40L decreased suppressive Treg function (p<0.05), without inducing Treg cell death. Treg suppressive function was restored when in vitro-generated SLE-DCs expressing OX40L were pre-incubated with a blocking anti-OX40L mAb. Furthermore, purified tonsils TFR cells previously cultured or not with sOX40L were cultured with purified TFH and memory B cells in the presence of SEB. We observed a higher immunoglobulin production and an increased differentiation of B cells into CD38⁺ plasmablasts in co-cultures with TFR exposed to sOX40L.

APCs from active SLE patients (n = 5) mediated Tregs dysfunction in an OX40L-dependent manner (mean % of inhibition 25.5±22 vs 72.9±9.6 with APCs purified from 7 HD, p=0.01). We also observed an inverse correlation between OX40L expression on SLE-APCs and their ability to hamper Tregs cell suppressive function (r=-0.85, p=0.0001).

OX40L-expressing cells co-localized with FoxP3 positive cells in active SLE skin lesions, suggesting that OX40L+ cells-Treg contact actually operates in vivo within inflammatory tissues.

In vitro, engagement of OX40L/OX40 axis resulted in FoxP3 down-regulation in Tregs. FoxP3 expression in SLE Tregs negatively correlated with the proportion of circulating OX40L-expressing mDCs, suggesting that OX40L-dependent Foxp3 down-regulation also operates in vivo.

Conclusion: These data support that OX40L/OX40 signals are implicated in T regulatory cell dysfunction in human SLE. Thus, blocking OX40L/OX40 axis appears as a promising therapeutic strategy.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/ox40ox40l-axis-impairs-follicular-and-natural-regulatory-t-cell-function-in-human-systemic-lupus/