Striking Dichotomy of PD-L1 and PD-L2 Pathways in Regulating Alloreactive CD4 super(+) and CD8 super(+) T Cells In Vivo

• Published in: American journal of transplantation Vol. 7; no. 12; pp. 2683 - 2692
• Main Authors: Habicht, A, Kewalaramani, R, Vu, MD, Demirci, G, Blazar, B R, Sayegh, M H, Li, X C
• Format: Journal Article
• Language: English
• Published: 01.12.2007
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2007.01999.x

Programmed death-1 (PD-1) is a recently identified coinhibitory molecule that belongs to the CD28 superfamily. PD-1 has two ligands PD-L1 and PD-L2. There is some evidence that PD-L1 and PD-L2 serve distinct functions, but their exact function in alloimmunity remains unclear. In the present study, we used a GVHD-like model that allows detailed analyses of T-cell activation at a single cell level in vivo to examine the role of PD-1-PD-L1 and PD-1-PD-L2 interactions in regulating proliferation of CD4 super(+) and CD8 super(+) T cells in response to alloantigen stimulation. We found that both CD4 super(+) and CD8 super(+) T cells proliferated vigorously in vivo and that PD-L1 and PD-L2 exhibit strikingly different effect on T-cell proliferation. While blocking PD-L1 did not affect the in vivo proliferation of CD4 super(+) and CD8 super(+) T cells regardless of CD28 costimulation, blocking PD-L2 resulted in a marked increase in the responder frequency of CD8 super(+) T-cells in vivo. The effect of PD-L2 on the CD8 super(+) T-cell proliferation is regulated by CD28 costimulation and by the CD4 super(+) T cells. We conclude that PD-L1 and PD-L2 function differently in regulating alloreactive T-cell activation in vivo, and PD-L2 is predominant in this model in limiting alloreactive CD8 super(+) T-cell proliferation.