Oral Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Adaptive and innate immune suppression by trimolecular CD52-HMGB1-Siglec complexes: a homeostatic role in autoimmune diabetes.   (#58)

Leonard C Harrison 1 , Esther Bandala-Sanchez 1 , Ralph M. Böhmer 1 , Julian J Bosco 1 , Alana M Neale 1 , Maryam Rashidi 1 , Reinwald Simone 1 , Stone L Stone 1 , Yuxia Zhang 1
  1. Walter and Eliza Hall Institute, Parkville, VIC, Australia

T cells use a range of mechanisms to regulate each other and maintain homeostasis. In testing the hypothesis that paracrine mechanisms limit T-cell proliferation we discovered that antigen-activated CD4+ T cells with high expression of the GPI-anchored glycoprotein CD52 suppress other T cells. CD52hi CD4+ T cells are distinct from CD4+CD25+FOXP3+ Treg cells by many criteria, including methylation at the FOXP3 locus and mode of action. Suppression is due to phospholipase C-mediated release of soluble CD52, which binds to the Siglec-10 receptor on human T cells, leading to decreased phosphorylation of T-cell receptor-associated tyrosine kinases Lck and ZAP-70, and impaired T-cell activation (1). CD52 was recovered from human T cells and monocytes complexed with the danger-associated molecular pattern molecule, HMGB1, and Siglec-10, and the tyrosine phosphatase SHP1.

Nanomolar concentrations of CD52-Fc suppressed the functions of T cells and innate immune cells (human monocytes, mouse bone marrow-derived macrophages and dendritic cells) by binding to Siglecs in the presence of HMGB1 (in serum). At higher concentrations, CD52-Fc induced caspase-dependent cell death. Direct studies with recombinant proteins showed that the interaction of CD52 with Siglec-10 required its prior binding of the B (pro-inflammatory) box of HMGB1. This mechanism not only captures HMGB1 to abrogate its pro-inflammatory effects but leads to concerted immunosuppression via Siglecs.

Humans with and at risk for type 1 diabetes had a reduced frequency and function of CD52hi CD4+ T cells generated specifically to the islet autoantigen GAD65. In NOD mice, adoptive transfer of CD52hi-depleted splenic lymphocytes from young, pre-diabetic mice lead to the rapid onset of diabetes.Treatment of NOD mice with CD52-Fc immediately at diabetes onset reversed hyperglycemia. These studies identify a previously unrecognized mechanism of adaptive and innate immune regulation that may protect against autoimmune diabetes, and reveal the therapeutic potential of CD52.

  1. (1) Bandala-Sanchez et al. Nat Immunol 14:741-748, 2013.