|Brown, Deborah - University Of Nebraska|
|Lampe, Anna - University Of Nebraska|
Submitted to: Frontiers in Immunology
Publication Type: Review Article
Publication Acceptance Date: 2/21/2016
Publication Date: 3/9/2016
Citation: Brown, D., Lampe, A.T., Workman, A.M. 2016. The differentiation and protective function of cytolytic CD4 T cells in influenza infection. Frontiers in Immunology. 7:93. doi:10.3389/fimmu.2016.00093
Interpretive Summary: Cytotoxic CD8 T cells have been recognized as the major contributor to the control of viral infection by lysing virally infected cells on which they recognize foreign antigen presented by MHC class I molecules. However, many viral infections lead to a dramatic down-regulation of MHC class I expression or otherwise prevent the presentation of MHC class I molecules on the cell surface, allowing them to escape CD8 T cell recognition. In contrast, CD4 T cells are described as playing an indirect role in anti-viral responses by secreting cytokines after recognizing viral peptides bound to MHC class II molecules. These cytokines promote CD8 T cell function, maintain CD8 T cell memory and induce high affinity antibody production by B cells. This helper function has been well characterized; however, recent studies indicate that CD4 T cells have a more direct role in anti-viral immune responses whereby they acquire the ability to lyse virally infected cells. MHC class II restricted CD4 T cells with cytolytic activity have been identified in peripheral blood of human subjects with various chronic infections and also in mouse models of both chronic and acute infection. This review highlights some of the early work describing this novel CD4 T cell subset and then details some of our recent work to characterize the differentiation and protective function of cytolytic CD4 T cells in protection against influenza A virus infection.
Technical Abstract: CD4 T cells that recognize peptide antigen in the context of Class II MHC can differentiate into various subsets that are characterized by their helper functions. However, increasing evidence indicates that CD4 cells with direct cytolytic activity play a role in chronic, as well as, acute infections such as influenza A virus (IAV) infection. In the last couple of decades, techniques to measure the frequency and activity of these cells has demonstrated their abundance in infections such as HIV, mouse pox, murine gamma herpes virus, CMV, EBV and influenza among others. We now appreciate a greater role for CD4 CTL as direct effectors in viral infections and anti-tumor immunity through their ability to acquire perforin mediated cytolytic activity and contribute to lysis of virally infected targets or tumors. As early as the 1980s, CD4 T cell clones with cytolytic potential were identified after influenza virus infection, yet much of this early work was dependent on in vitro culture and little was known about the physiological role of CD4 cytolytic T cells (CD4 CTL). Here, we discuss the direct role of CD4 CTL in protection against lethal IAV infection and the factors that drive the generation of perforin mediated lytic activity in CD4 cells vivo during IAV infection. While focusing on CD4 CTL generated during IAV infection, we pull comparisons from the literature in other anti-viral and anti-tumor systems. Further, we highlight what is currently known about CD4 CTL secondary and memory responses, as well as vaccination strategies to induce these potent killer cells that provide an extra layer of cell mediated immune protection against heterosubtypic IAV infection.