Th17-dependent autoimmune responses can develop after heart or lung transplantation, and are associated with fibro-obliterative forms of chronic rejection. However, the specific self-antigens involved are typically different from those associated with autoimmune disease. To investigate the basis of these responses, we questioned whether removal of Tregs or blockade of function reveals a similar auto-antigen bias. We found that Th17 cells specific for collagen type V (Col V), kα-1-tubulin, and vimentin were present in healthy, adult PBMC, cord blood, and fetal thymus. Using synthetic peptides and recombinant fragments of the Col V triple helical region (α1V), we compared Th17 cells from healthy donors with Th17 cells from Col V-reactive heart and lung patients. While the latter responded well to α1(V) fragments and peptides in a DR–restricted fashion, Th17 cells from healthy individuals responded in a DR-restricted fashion to fragments, but not to peptides. Col V, kα-1-tubulin, and vimentin are preferred targets of a highly conserved, hitherto unknown, pre-existing Th17 response that is MHCII-restricted. These data suggest that autoimmunity after heart and lung transplantation may result from dysregulation of an intrinsic mechanism controlling airway and vascular homeostasis.