Nuclear shelter: The influence of subcellular location on the processing of antigens by macroautophagy

CD4(+) T cells recognize peptides displayed by MHC II molecules on the surface of specialized antigen-presenting cells (APCs). These peptides are generally considered to come from exogenous proteins that have been internalized by APCs and degraded in the endocytic network, thus representing a snapshot of proteins in the APC's extracellular environment. However, it is increasingly apparent that some proteins endogenously expressed within the APC itself can directly gain access to the MHC II pathway. This has particular implications for pathogens that naturally infect APCs, since such infections might therefore become visible to CD4(+) (MHC II-restricted) effector T cells. Such a pathogen is Epstein-Barr Virus (EBV), a human herpesvirus that infects most individuals establishing life-long infection of B cells. EBV's persistence in the immune host depends upon expression of the viral nuclear protein EBNA1 to segregate the viral genome into daughter cells during homeostatic B cell turnover. Surprisingly, EBNA1 contains many CD4 epitopes, elicits strong CD4 T cell responses in most people and, in in vitro models, can be processed for CD4(+) T cell recognition through delivery into the MHC II pathway, apparently via macroautophagy (hereafter referred to as autophagy). Taken together, these observations raise the interesting question of how does EBV persist in the B cell system given the presence of strong CD4 T cell responses directed against the one protein the virus absolutely requires for long-term persistence?