Enhancement of suppressive function of Ly49⁺ CD8⁺ T cells in allogeneic immunity by CD80/86-CD28 blockade in mouse

Ly49⁺ CD8⁺ T cells restricted by Qa-1 or major histocompatibility complex (MHC)/peptide can function as immune suppressors in autoimmune diseases and chronic activation-associated tissue damage. In organ transplantation, a C-X-C motif chemokine receptor 5⁺ (CXCR5⁺) Ly49⁺ CD8⁺ T cell subset reportedly suppresses CD4⁺ T cell activation via Qa-1 recognition, thereby inhibiting donor-specific antibody (DSA) production and promoting heart graft survival, particularly under CD80/86-CD28 co-stimulation blockade. However, their precise role in anti-allogeneic responses remains unclear.

We examined Ly49⁺ CD8⁺ T cell function in a murine cardiac transplant model and mixed lymphocyte reactions (MLRs), with or without antagonistic anti-CD80/86 monoclonal antibodies (mAbs).

Both Ly49⁺ and Ly49^- CD8⁺ T cells infiltrated grafts and produced IFN-γ. Anti-CD80/86 mAb treatment prolonged graft survival, reduced IFN-γ production, increased infiltration of cytotoxic Ly49⁺ CD8⁺ T cells, and upregulated immunosuppressive gene expression in accepted grafts. In MLRs, Ly49⁺ CD8⁺ T cells showed greater proliferation and IFN-γ production than Ly49^- counterparts. Qa-1 blockade had no effect, whereas anti-CD80/86 mAb induced anergy. Ly49⁺ CD8⁺ T cells obtained after MLR with anti-CD80/86 mAbs were hyporesponsive to restimulation but exerted enhanced cytotoxicity against activated autologous T cells partly via Qa-1 interaction. Furthermore, these Ly49⁺ CD8⁺ T cells expressed lymphocyte activation gene-3 (LAG-3) and cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), which contributed to the suppression of T cell proliferation.

Ly49⁺ CD8⁺ T cells function as effectors in anti-allogeneic responses. CD80/86-CD28 blockade suppresses their effector functions while enhancing their Qa-1-dependent regulatory activity toward activated autologous T cells.