Th17 Responses to Collagen Type V, kα1-Tubulin, and Vimentin Are Present Early in Human Development and Persist Throughout Life

Abstract

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.

Leukocyte-Associated Ig-like Receptor 1 Inhibits Th1 Responses but Is Required for Natural and Induced Monocyte-Dependent Th17 Responses

“…We have shown that the natural T h 17 response to ColV can be induced by the 160-aa-long ColV a1 fragments but not the 15mer peptides of ColV (9). Additionally, in this study, we have demonstrated that sLAIR1/Fc binds the ColV fragment but not the peptide (Fig.…”

“…We first sought to determine whether B6 mice (background of the LAIR1 2/2 mice) had pre-existing responses to ColV, similar to those reported for the CBA mice (9). Using the trans-vivo bioassay system we demonstrated that whole spleen cells from naive wild-type (WT) B6 mice did not respond to ColV (Fig.…”

“…Recently, we have described pre-existing or natural T h 17 responses to certain self-antigens, including ColV, vimentin, and K-a1-tubulin in normal healthy individuals and in naive CBA mice (9). These pre-existing responses could be detected after the removal of CD39 + or CD25 + T regulatory (T reg ) cells or by the neutralization of TGF-b1 (9). Interestingly, these T h 17 cells responded in an HLA-DR-specific fashion to 160-aa fragments of ColV a1, but not to 15mer ColV peptides (9).…”

“…These pre-existing responses could be detected after the removal of CD39 + or CD25 + T regulatory (T reg ) cells or by the neutralization of TGF-b1 (9). Interestingly, these T h 17 cells responded in an HLA-DR-specific fashion to 160-aa fragments of ColV a1, but not to 15mer ColV peptides (9). Thus, some tertiary structure was required for the natural T h 17 response.…”

A Humanized Mouse Model Generated Using Surplus Neonatal Tissue

“…Using the trans vivo delayed-type hypersensitivity assay, we show that NeoThy T cells mount a collagen V-specific effector response to co-injected antigen in the presence of anti-transforming growth factor β neutralizing antibody. This demonstrates the utility of the NeoThy for study of innate-like Th17 cell function in the context of iPSC immunogenicity ( Sullivan et al., 2017 ). Last, NeoThy mice challenged with a B6 skin graft mounted rejection responses characterized by the two metrics of (1) hCD3 + T cell infiltration and (2) visible graft loss over time, similar to fetal tissue controls ( Figures 3 D and 3E).…”