CTLA-4: a negative regulator of autoimmune disease.

TLDR

CTLA‑4, a CD28 homologue that binds B7‑1/B7‑2, is expressed on activated T cells and is involved in murine relapsing‑remitting experimental autoimmune encephalomyelitis, a PLP139‑151‑specific CD4⁺ T‑cell mediated demyelinating disease in SJL/J mice. This study aimed to examine the role of CTLA‑4 in regulating autoimmune disease. Anti‑CTLA‑4 antibodies enhanced in vitro proliferation and cytokine production of PLP139‑151‑primed lymph node cells, increased the ability of T cells to transfer disease, accelerated and exacerbated disease in vivo, and worsened relapses during remission, indicating that CTLA‑4 downregulates ongoing immune responses and plays a major role in regulating autoimmunity.

Abstract

CTLA-4, a CD28 homologue expressed on activated T cells, binds with high affinity to the CD28 ligands, B7-1 (CD80) and B7-2 (CD86). This study was designed to examine the role of CTLA-4 in regulating autoimmune disease. Murine relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) is a demyelinating disease mediated by PLP139-151-specific CD4+ T cells in SJL/J mice. Anti-CTLA-4 mAbs (or their F(ab) fragments) enhanced in vitro proliferation and pro-inflammatory cytokine production by PLP139-151-primed lymph node cells. Addition of either reagent to in vitro activation cultures potentiated the ability of T cells to adoptively transfer disease to naive recipients. In vivo administration of anti-CTLA-4 mAb to recipients of PLP139-151-specific T cells resulted in accelerated and exacerbated disease. Finally, anti-CTLA-4 treatment of mice during disease remission resulted in the exacerbation of relapses. Collectively, these results suggest that CTLA-4 mediates the downregulation of ongoing immune responses and plays a major role in regulating autoimmunity.