Impaired selectin-dependent leukocyte recruitment induces T-cell exhaustion and prevents chronic allograft vasculopathy and rejection.

T-cell exhaustion limits the immune response against chronic infections and tumors. Reinvigorating exhausted T cells promotes clearance of infections and tumors. There are several ongoing clinical trials to harness the potential of reinvigorated T cells for the treatment of chronic infections and tumors by reversing T-cell exhaustion. However, the mechanisms leading to T-cell exhaustion are unknown. Further, the role of T-cell exhaustion in transplantation or autoimmunity is not defined. Here we show that impaired leukocyte recruitment leads to CD4 T-cell exhaustion as a novel mechanism of transplant tolerance. Strategies targeting leukocyte recruitment may prevent allograft rejection and promote tolerance. On the other hand, promoting leukocyte recruitment may prevent T-cell exhaustion and enhance tumor/microbe immunity.