Leukocyte-associated Ig-like receptor 1 inhibits T_h1 Responses but is required for natural and induced monocyte-dependent T_h17 responses

Leukocyte-associated Ig-like receptor 1 (LAIR1) is an ITIM-bearing collagen receptor expressed by leukocytes and is implicated in immune suppression. However, using a divalent soluble LAIR1/Fc recombinant protein to block interaction of cell surface LAIR1 with matrix collagen, we found that whereas T_h1 responses were enhanced as predicted, T_h17 responses were strongly inhibited. Indeed, LAIR1 on both T cells and monocytes was required for optimal T_h17 responses to collagen type (Col)V. For pre-existing “natural” T_h17 response to ColV, the LAIR1 requirement was absolute, whereas adaptive T_h17 and T_h1/17 immune responses in both mice and humans were profoundly reduced in the absence of LAIR1. Furthermore, the addition of C1q, a natural LAIR1 ligand, decreased T_h1 responses in a dose-dependent manner, but it had no effect on T_h17 responses. In IL-17–dependent murine organ transplant models of chronic rejection, LAIR1^+/+ but not LAIR1²/² littermates mounted strong fibroproliferative responses. Surface LAIR1 expression was higher on human T_h17 cells as compared with T_h1 cells, ruling out a receptor deficiency that could account for the differences. We conclude that LAIR1 ligation by its natural ligands favors T_h17 cell development, allowing for preferential activity of these cells in collagen-rich environments. The emergence of cryptic self-antigens such as the LAIR1 ligand ColV during ischemia/reperfusion injury and early acute rejection, as well as the tendency of macrophages/ monocytes to accumulate in the allograft during chronic rejection, favors T_h17 over T_h1 development, posing a risk to long-term graft survival.