CD154 is a negative regulator of autoaggressive CD8⁺T cells in type 1 diabetes

Abstract

TNF͞CD80 mice, a CD8 ؉ T cell-mediated model for type 1 diabetes, transgenically express tumor necrosis factor ␣ (TNF-␣) and the costimulatory molecule CD80 in their pancreatic islets. Here we show that these molecules bypass the need for CD40 -CD154 costimulatory interactions in activation of CD8 ؉ T cells, allowing us to determine the role of CD40 -CD154 signals in regulation of autoaggressive CD8 ؉ T cells after their in vivo priming. TNF͞CD80 CD154-deficient mice rapidly develop diabetes, whereas CD154-sufficient mice do not. This finding correlates with the decreased numbers of CD4 ؉ CD25 ؉ T regulatory (TR) cells in the islets and pancreatic lymph nodes, in comparison to disease-protected CD154-sufficient mice. Administration of a CD40 agonistic antibody induces a systemic and tissue-specific increase in T R cells. However, this increase fails to delay diabetes development in the absence of CD154. Adoptive transfer studies show that CD8 ؉ T cells from TNF͞CD80 CD154-deficient, but not CD154-sufficient, mice are resistant to regulation in vivo. This study provides evidence that CD40-transduced signals initiate T R cell increase in vivo and that CD154-transduced signals sensitize autoaggressive CD8 ؉ T cells to suppression.T he deletion of self-reactive T cells by thymic negative selection is not complete, leading to release of cells with autoimmune potential into the periphery (1). Type 1 diabetes (T1D) is an autoimmune disease in which lymphocytic infiltration of the islets of Langerhans, a process termed insulitis, is followed by T cell-mediated destruction of the insulin-producing beta cells of the pancreas (2).It has been demonstrated by in vivo depletion studies that beta cell destruction, in mouse models of T1D, is mediated by CD8 Because of this critical role for CD40-CD154 signals in the priming phase of immune responses, investigations have centered on ablation of this pathway for the prevention of autoimmune disease (9-11) and transplant rejection (12)(13)(14).Inflammation resulting from viral infections has long been associated with development of autoimmunity (15). In particular, the proinflammatory cytokine tumor necrosis factor ␣ (TNF-␣) plays an important role in the pathogenesis of several autoimmune diseases, including T1D. CD40-CD154 blockade or CD154 deficiency in nonobese diabetic (NOD) mice prevents insulitis and T1D (10). However, this protection can be overcome by systemic administration, or constitutive islet-specific expression of TNF-␣ from a rat insulin promoter (RIP-TNF-␣) (16,17). The presence of TNF-␣ bypasses the requirement for CD40-CD154 interactions in priming and differentiation of islet-specific CD8 ϩ T cells in CD154-deficient RIP-TNF-␣ NOD mice (18).Recently, a unique population of thymic-derived T regulatory (T R ) cells has been identified and shown to suppress activation of autoreactive T cells (19,20). Phenotypic characterization of T R cells includes expression of CD4, CD25 (21), and CTLassociated antigen 4 (22). T R cell development and function depend on the tran...

Foxp3+regulatory T cells promiscuously accept thymic signals critical for their development

“…In mice deficient in this pathway, there is an absence of Ig class switching and germinal center formation. More recently, a severe reduction in the CD4 ϩ CD25 ϩ Treg population also has been observed (16)(17)(18)(19). To assess the role of CD40-CD154 in Foxp3 ϩ Treg development and homeostasis, we investigated Foxp3 ϩ CD4 ϩ T cells in WT, CD40 Ϫ/Ϫ , and CD154 Ϫ/Ϫ mice.…”

Differential effect of agonistic anti-CD40 on human mature and immature dendritic cells: the Janus face of anti-CD40

“…52 An immunosuppressive effect of CD40/CD40 ligand interaction has also been observed in transgenic TNF/CD80 mice, a model of type 1 diabetes, expressing TNF-␣ and the costimulatory molecule CD80 in their pancreatic islets. 15 Finally, our results suggest that CD40 mAb-based immunotherapy, through its differential effect on DCs, may have more complex effects than previously thought, calling for added caution. Indeed, anti-CD40 intervention might disrupt not only the deleterious peripheral tolerance of certain tumors or pathogens but also the beneficial natural tolerance of self antigens, creating a risk of autoimmunity.…”

“…[5][6][7][8][9][10][11] The observed tumor regression may be induced by potentiation of antitumoral T-cell responses or apoptosis of CD40 ϩ malignant cells. [5][6][7][8][9][10]12 Unexpectedly, agonistic anti-CD40 monoclonal antibodies (mAbs) and CD40 ligand also exerted an immunosuppressive action in models of collagen-induced arthritis, 13 melanoma, 14 and type 1 diabetes, 15 pointing to a dual function of CD40 agonists. 16 CD40 agonists may act on T-cell responses by modulating antigen presentation by DCs.…”

A 20-Mb Region of Chromosome 4 Controls TNF-α-Mediated CD8+ T Cell Aggression Toward β Cells in Type 1 Diabetes

“…Nevertheless, it remains to be seen whether there is a relationship between localized intraislet TNF-␣ and accelerated T1D at the level of the functionality of CD4 ϩ Foxp3 ϩ T cells, or the sensitivity of the intraislet CD8 ϩ T cells to be regulated by them (26). Interestingly, we documented a substantial decrease in the percentage of CD3 ϩ CD4 Ϫ CD8 Ϫ T cells in the islets of TNF-␣-NOD and TNF-␣-Idd3.Idd5 mice compared with their nontransgenic NOD and NOD-Idd3.Idd5 littermates, respectively (Fig 3).…”