Critical Role for CD39+ Tregs in Humans and Non-Human Primates in Peripheral Tolerance to SALSAAs.

Abstract

Self Antigens Left Sequestered After Activation [SALSAAs] represent a class of autoantigens that are transiently made available to the immune system during immunologic activation of tissues, and subsequently are rendered inaccessible following repair and return to a resting state. Since injury/repair processes are common events within tissues, the immune response to SALSAAs must remain under strict control, to avoid a potentially deadly spiral of fibro-obliterative pathologies. Guided by reports of specific self antigens that have been found to be targeted during cardiac allograft vasculopathy & obliterative bronchiolitis, we used a trans-vivo DTH assay(tvDTH) -based, “tolerance-breaking” approach, to identify the immunodominant SALSAAs of mammalian hosts. In normal PBMC, TGFβ neutralization, or removal of CD39+ or CD25+ Tregs, revealed a remarkably strong footpad swelling response to: a) components of the “pro-inflammatory matrix”, such as collagen type V (Col V), and its homologue Col XI; b) cytoskeletal proteins like Vimentin and kα1-tubulin; and c) HSP65. In contrast, no response to ubiquitous collagens I,II & IV, or to cardiac myosin or myelin basic protein was revealed. Strong tvDTH responses to SALSAAs were obtained in normal human and NHP controls, and to a lesser extent, in rats and mice, by removal of CD39+ or CD25+ Tregs, by drugs blocking CD39 ATPase activity or adenosine receptor A2b, or by mAb neutralization of TGFβ1 or IL-35. Neutralization of IL-17, or addback of CD39+ T cells restored low responses to SALSAAs. Conclusion: Since only primed/ memory T effector cells can mediate a tvDTH response to antigen, the strong response to SALSAAs revealed in normal human & NHP subjects by removal of CD39+ Tregs implies that T cells primed to these specific self antigens were not deleted in the thymus. Peripheral tolerance therefore requires homeostasis between SALSAA-specific Th17 effector and CD39+ Treg populations. Imbalance between Th17 effector and CD39+ Treg populations, both donor and host-derived, may account for autoimmunity to SALSAAs post-transplant, associated with primary graft dysfunction and chronic rejection. It may also be the cause of native organ failure, as in Col V-driven coronary atherosclerosis and idiopathic pulmonary fibrosis. DISCLOSURE:Wilkes, D.: Other, Immune Works, Founder and CEO of company.