Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand

Abstract

Costimulatory signals received by diabetogenic T cells during priming by or upon secondary encounter with autoantigen are decisive in determining the outcome of autoimmune attack. The OX40-OX40 ligand (OX40L) costimulatory pathway is known to influence T cell responses, prompting us to examine its role in autoimmune diabetes. A null allele at OX40L completely prevented diabetes development in nonobese diabetic mice and strongly reduced its incidence in a TCR transgenic model (BDC2.5). However, somewhat paradoxically, the initial activation of T cells responsive to islet β cell Ag was slightly faster and more efficient in the absence of OX40L, with an increased degree of cell proliferation and survival in the deficient hosts. Activated T cell migration into and retention within the islets was also slightly accelerated. When challenged in vitro, splenocytes from BDC2.5.OX40Lo/o mice showed no altered reactivity to exogenously added peptide, no bias to the Th1 or Th2 phenotype, and no alteration in T cell survival. Thus, the OX40/OX40L axis has the paradoxical effect of dampening the early activation and migration of autoimmune T cells, but sustains the long-term progression to autoimmune destruction.

Thymic Stromal Lymphopoietin and Thymic Stromal Lymphopoietin–Conditioned Dendritic Cells Induce Regulatory T-Cell Differentiation and Protection of NOD Mice Against Diabetes

“…This possibility was supported by the findings of enhanced induction of Foxp3 ϩ T-cells when the OX40L/OX40 signaling pathway was blocked (G.B., S.G., G.D., A.A., unpublished data). Moreover, the involvement of the OX40/OX40L pathway in diabetes was consistent with previous reports of diabetes protection in NOD mice treated with anti-OX40L antibodies and in OX40L Ϫ/Ϫ NOD mice (49,50). These data suggested the important role of OX40/OX40L interaction in the differentiation of Tregs and the protection against diabetes observed here in TSLP-DCs transferred NOD mice.…”

OX40 ligand shuts down IL-10-producing regulatory T cells

“…These results were supported by in vivo studies showing that blocking OX40͞OX40L interaction prevents the induction and maintenance of TH2-mediated allergic immune responses (21)(22)(23). However, other studies revealed that blocking OX40͞OX40L interaction ameliorates or prevents TH1-mediated diseases (24)(25)(26). Furthermore, administration of soluble OX40L or gene transfer of OX40L into tumors has been shown to strongly enhance antitumor immunity in mice (27,28).…”

T Cells in Atherogenesis

“…This costimulatory pair is induced by IL-12, it is important for development and survival of memory CD4 ϩ T cells and is implicated in several autoimmune diseases including diabetes and multiple sclerosis, 78,79 and also in atherosclerosis. 80 Overexpression of Ox40L in fat-fed mice increased fatty streak formation, whereas Ox40L Ϫ/Ϫ mice exhibited smaller lesions than did controls.…”