%0 Journal Article %A Bhadra, Rajarshi %A Cobb, Dustin A. %A Khan, Imtiaz A. %D 2013 %I Begell House %K PD-1, CD8 exhaustion, CD40, infectious disease %N 4 %P 361-378 %R 10.1615/CritRevImmunol.2013007444 %T CD40 Signaling to the Rescue: A CD8 Exhaustion Perspective in Chronic Infectious Diseases %U https://www.dl.begellhouse.com/journals/2ff21abf44b19838,76b442880fa199cc,1ee707b618c8c11f.html %V 33 %X Chronic infectious diseases such as HIV, HBV, and HCV, among others, cause severe morbidity and mortality globally. Progressive decline in CD8 functionality, survival, and proliferative potential-a phenomenon referred to as CD8 exhaustion-is believed to be responsible for poor pathogen control in chronic infectious diseases. While the role of negative inhibitory receptors such as PD−1 in augmenting CD8 exhaustion has been extensively studied, the role of positive costimulatory receptors remains poorly understood. In this review, we discuss how one such costimulatory pathway, CD40−CD40L, regulates CD8 dysfunction and rescue. While the significance of this pathway has been extensively investigated in models of autoimmunity, acute infectious diseases, and tumor models, the role played by CD40−CD40L in regulating CD8 exhaustion in chronic infectious diseases is just beginning to be understood. Considering that monotherapy with blocking antibodies targeting inhibitory PD−1−PD−L1 pathway is only partially effective at ameliorating CD8 exhaustion and that humanized CD40 agonist antibodies are currently available, a better understanding of the role of the CD40−CD40L pathway in chronic infectious diseases will pave the way for the development of more robust immunotherapeutic and prophylactic vaccination strategies. %8 2013-07-30