Galectin 3 as a regulator of and#947; herpesvirus specific CD8 T cell immunity and the utility of single domain antibodies

Abstract

The study was planned to gain insights into the molecular mechanisms and pathways newlineinvolved in differentiating CD8 + T cells during and#947;-herpesvirus infection. These viruses are newlinespecies-specific and hence are studied in a specific host. Murine herpesvirus 68 serve as one newlineof the most accessible model system. newlineCD8 + T cells are critically involved in controlling intracellular infections such as newlinethose caused by viruses. A comprehensive transcriptomic analysis of and#947;-herpesvirus newline(MHV68)-specific TCR transnuclear (TCR-TN) CD8 + T cells, that were obtained somatic newlinecell nuclear transfer (SCNT) approach, was performed. These cells are considered as newlinephysiologically relevant population because of their method of generation that requires no newlinetransgenesis. We observed differential expression of several thousand transcripts in and#947;-HV newlineexpanded CD8 + T cells as compared to their naïve counterparts encompassing various newlinepathways and forming different networks. Activated cells highly upregulated galectin-3, a newlinemember protein of galectin family. We therefore explored the role of galectin-3 in newlineinfluencing anti-MHV68 immunity and demonstrated its recruitment intracellularly at newlineimmunological synapse (IS) during CD8 + T cell activation. By virtue of its presence at the IS, newlinegalectin-3 constrained T cell activation, proliferation and functionality. The localization of newlinegalectin-3 to IS was evident both in the naïve and memory CD8 + T cells responding through newlinetheir TCRs or the coreceptors suggesting for its role as an intrinsic negative regulator. newlineAccordingly, animals lacking galectin-3 signal because of gene knockout mounted a stronger newlineMHV68-specific CD8 + T cell response to the majority viral epitopes displayed by different newlineMHC haplotypes. The enhanced effector CD8 + T cell response led to a better viral control. newlineThis study therefore established galectin-3 as a potential intracellular target in and#947;-herpesvirus newlinespecific CD8 + T cells whose function could be disrupted to enhance antiviral immunity.