Elucidating the roles of PD-L1 and PD-L2 costimulation on T cell activation, differentiation and effector function.

摘要

Members of the B7/CD28 superfamily are known to regulate T cell responses by delivering signals that can enhance or inhibit T cell activation. Within this superfamily, the PD-1:PD-L1/PD-L2 pathway currently consists of one receptor, PD-1, and two ligands, PD-L1 and PD-L2. The functions of these molecules are still unclear. In this thesis, I have elucidated the roles of PD-L1 and PD-L2 in regulating T activation, differentiation and effector function. To begin to understand their functions, I first characterized the expression of PD-1, PD-L1 and PD-L2 in vivo and the stimuli that induce their expression. These studies indicated that PD-L1 and PD-L2 have distinct expression patterns with PD-L1 being expressed more broadly than PD-L2. To determine the obligatory functions of PD-L1 and PD-L2, I utilized PD-L1 deficient, PD-L2 deficient and PD-L1/PD-L2 double deficient mice and performed a comparative analyses as to ascertain unique, as well as overlapping functions, for these two PD-1 ligands. Using antigen-specific T cells, I revealed synergistic roles for PD-L1 and PD-L2 in limiting IL-2 and IFN-gamma production, as well as Th1 differentiation, with PD-L1 playing a greater role than PD-L2. In vivo, PD-L1 and PD-L2 can also regulate Th differentiation. PD-L1 and PD-L2 deficiency during infection with Leishmania mexicana or during allergen induced airway disease resulted in an increase in Th1 responses relative to Th2 in vivo. I further demonstrated that PD-L1 or PD-L2 deficiency in the effector phase of allergen airway disease resulted in decreased airway hyperresponsiveness and pulmonary inflammation, suggesting that these ligands can act directly within peripheral tissues. In addition to inhibiting T cell function, PD-L1 and PD-L2 can limit B cell responses and immunoglobulin production. Finally, I evaluated aged C57BL/6 PD-L1/PD-L2 double deficient mice for the development of autoimmune disease and demonstrated that these mice develop characteristics of a lupus-like disease, similar to the disease that develops in PD-1 deficient mice. Taken together, my work demonstrates that PD-L1 and PD-L2 can synergistically limit T cell activation and Th1 differentiation and regulate immune responses during infection, allergy and autoimmunity.