We and others have reported that autoimmunity to the self antigen Collagen V (ColV) after lung transplantation, is strongly correlated with the development of Bronchiolitis Obliterans Syndrome, the clinical manifestation of obliterative bronchiolitis and the main cause of mortality and graft loss. In addition, we have shown that ColV autoimmunity is a Th17 dependent process, as antibody to IL17 and CD4, but not to IFNΓ or CD8, blocked the response. In normal individuals, approximately 50% of circulating Tregs express the extracellular ATPase CD39. This subset is thought to play a key role in maintaining self tolerance by suppressing Th17-associated autoimmunity. With this in mind, we set out to investigate if ColV specific Th17 cells are present in normal, healthy individuals. We collected PBMCs for use in trans-vivo-DTH and intracellular cytokine staining assays. Results: ColV reactivity in whole PBMC of healthy subjects was low, but significantly higher than the response to Collagen type I. We found that the removal of CD39⁺ T cells from normal PBMC revealed strong ColV reactivity. In addition, the removal of CD39⁺ T cells from Tcell-monocyte co-cultures uncovered a ColV-induced production of IL-17, albeit at lower levels/CD4Tcell as compared to ColV-sensitized lung transplant recipients. Furthermore, the Th17 “natural” response in CD39^– Tcells was also found to occur selectively in response to k-Α-tubulin, HSP65 and vimentin, but not in response to cardiac myosin, Collagen type IV, myelin basic protein or prostatic acid phosphatase (see Figure 1).

Conclusion: Our data strongly implies that CD39⁺ Tregs restrain ColV autoimmunity in normal, healthy individuals. The “natural” ColV-reactive Th17-like cells may represent a novel class of autoreactive T cell that is released from CD39⁺ Treg control after lung transplant, compromising graft survival.

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