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

Natalia Martin-Orozco, Zhibin Chen, Laurent Poirot, Elzbieta Hyatt, Andy Chen, Osami Kanagawa, Arlene Sharpe, Diane Mathis, Christophe Benoist

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.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.

Original languageEnglish (US)
Pages (from-to)6954-6960
Number of pages7
JournalJournal of Immunology
Volume171
Issue number12
StatePublished - Dec 15 2003
Externally publishedYes

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OX40 Ligand
T-Lymphocytes
Cell Survival
Inbred NOD Mouse
Autoantigens
Type 1 Diabetes Mellitus
Islets of Langerhans
Cell Movement
Alleles
Cell Proliferation
Phenotype
Peptides
Incidence

ASJC Scopus subject areas

  • Immunology

Cite this

Martin-Orozco, N., Chen, Z., Poirot, L., Hyatt, E., Chen, A., Kanagawa, O., ... Benoist, C. (2003). Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand. Journal of Immunology, 171(12), 6954-6960.

Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand. / Martin-Orozco, Natalia; Chen, Zhibin; Poirot, Laurent; Hyatt, Elzbieta; Chen, Andy; Kanagawa, Osami; Sharpe, Arlene; Mathis, Diane; Benoist, Christophe.

In: Journal of Immunology, Vol. 171, No. 12, 15.12.2003, p. 6954-6960.

Research output: Contribution to journalArticle

Martin-Orozco, N, Chen, Z, Poirot, L, Hyatt, E, Chen, A, Kanagawa, O, Sharpe, A, Mathis, D & Benoist, C 2003, 'Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand', Journal of Immunology, vol. 171, no. 12, pp. 6954-6960.
Martin-Orozco N, Chen Z, Poirot L, Hyatt E, Chen A, Kanagawa O et al. Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand. Journal of Immunology. 2003 Dec 15;171(12):6954-6960.
Martin-Orozco, Natalia ; Chen, Zhibin ; Poirot, Laurent ; Hyatt, Elzbieta ; Chen, Andy ; Kanagawa, Osami ; Sharpe, Arlene ; Mathis, Diane ; Benoist, Christophe. / Paradoxical Dampening of Anti-Islet Self-Reactivity but Promotion of Diabetes by OX40 Ligand. In: Journal of Immunology. 2003 ; Vol. 171, No. 12. pp. 6954-6960.
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