Paradoxical dampening of anti-islet self-reactivity but promotion of diabetes by OX40 ligand.
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 beta 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.OX40L(o/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.
Martin-Orozco
Natalia
N
Section on Immunology and Immunogenetics, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.
Chen
Zhibin
Z
Poirot
Laurent
L
Hyatt
Elzbieta
E
Chen
Andy
A
Kanagawa
Osami
O
Sharpe
Arlene
A
Mathis
Diane
D
Benoist
Christophe
C
D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D007108:Immune Tolerance / Q000235:genetics; D016130:Immunophenotyping; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053278:OX40 Ligand; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism*; D048069:Tumor Necrosis Factors
D001324:Autoantigens; D008024:Ligands; D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D015375:Receptors, Interleukin-2; C504586:Tnfsf4 protein, mouse; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D048069:Tumor Necrosis Factors