Lymphoid and extralymphoid CD4 T cells that orchestrate the antiviral immune response

This review summarizes the present understanding of the biology of CD4 T cells during both the acute and memory phases of the response to nonpersisting viral infection. Elucidating the precise role of CD4 T cells in viral infections has been a challenge due to characteristics intrinsic to the CD4 response and the slow development of tools that allow accurate identification of the virus-specific cells in vitro and in vivo. This is especially apparent in comparison with antiviral CD8 T cells, for which immunologists possess many tools for tracking the cells throughout a response. However, recent developments in technology to follow antigen-specific CD4 T cells in virus infections have improved our understanding greatly. Ex vivo technologies such as the enzyme-linked spot forming assays and more recently the FluoroSPOT assays, cytokine capture and the advent of class II major histocompatibility complex multimers have improved our ability to accurately enumerate the virus-specific CD4 T-cell response. The development of virus-primed T-cell receptor transgenic CD4 T cells and imaging technologies that take advantage of allotype marking and luciferase or fluorescent transgenes now allow for high-resolution tracking of virus-specific CD4 T cells in many tissues. Inspite of these new technologies, many questions remain regarding the dynamics of CD4 memory T-cell populations and their contribution to immune protection against viral infections.