Dr. Donna Farber Research

Memory CD4 T cells and Immune responses to influenza virus | Mapping the Human Immune Response Signaling pathways for memory CD4 T cell recall and homeostasis

 

Memory CD4 T cells and Immune responses to influenza virus
 

Memory CD4 and CD8 T cells are generated in response to viral infection, persist long-term in vivo in diverse tissues, and mediate robust secondary responses upon viral challenge which are kinetically, spatially and functionally distinct from primary T cell responses (1). The potent effector responses of virus-specific memory CD8 T cells and their role in anti-viral protective responses has been well-characterized; however, considerably less is known about the function of memory CD4 T cells in anti-viral immunity. Memory CD4 T cells can play multiple roles in coordinating secondary responses via their direct effector functions, and their ability to “help” or promote cellular and humoral responses. Many highly variable pathogens such as influenza virus evade antibody-based vaccines, and therefore elucidating the diverse capacities of memory CD4 T cells in anti-viral immunity is a crucial step in the development of broad-based T cell-mediated immunity that will provide protection against infection with variant or new influenza strains that present a serious public health threat. Moreover, memory CD4 T cells directed against influenza persist in the periphery and lung of older children and adults, with the potential to mediate “first-line” immunity to viral challenge, particularly at the site of infection. Understanding how protective memory CD4 T cells are formed, and how memory CD4 T cells in diverse tissue compartments contribute to pathogen control or immunopathology are critical issues for optimizing immunity to influenza and other viral pathogens.

We have developed a novel mouse model in which immune responses to influenza virus are directed by virus-specific memory CD4 T cells in an otherwise naive mouse host, revealing new insights into how memory CD4 T cells coordinate anti-viral immunity (2-3). We found that memory CD4 T cells mediated efficient lung viral clearance, yet also promoted extensive immunopathology, clinical morbidity and reduced lung function (2, 4). These results indicate that memory CD4 T cells exemplify the dual nature of anti-viral responses in which protection can be masked by immunopathology, and recapitulate clinical responses to influenza virus, where immunopathology is now recognized as the underlying cause of pneumonia and death from pandemic strains. We further demonstrate that the balance of protection and immunopathology in secondary responses to influenza virus can be shifted by altering the tissue distribution, homing capacities, and expansion of memory CD4 T cells. In addition, we have identified a novel, tissue-resident subset of memory CD4 T cells in the lung that are retained in lung tissue and exhibit more effector functions and less proliferative capacities than lymphoid or spleen-resident memory CD4 T cells (5). These lung-resident memory CD4 T cells further promote optimal protective responses to influenza virus infection and protect form lethal viral doses. Our goals are to elucidate the functional and spatial mechanisms for anti-viral protection and immunopathology by memory CD4 T cells. Results from our research can lead to the design of strategies to improve the clinical outcome of viral infections by targeting pre-existing memory T cell responses, and optimizing generation of protective memory functions.

References
1. Verhoeven, D., J. R. Teijaro, and D. L. Farber. 2008. Heterogeneous Memory T Cells in Antiviral Immunity and Immunopathology. Viral Immunol 21:99-113.
2. Teijaro, J. R., M. N. Njau, D. Verhoeven, S. Chandran, S. G. Nadler, J. Hasday, and D. L. Farber. 2009. Costimulation modulation uncouples protection from immunopathology in memory T cell responses to influenza virus. J Immunol 182:6834-6843.
3. Teijaro, J. R., D. Verhoeven, C. A. Page, D. Turner, and D. L. Farber. 2010. Memory CD4 T cells direct protective responses to influenza virus in the lungs through helper-independent mechanisms. J Virol 84:9217-9226.
4. Verhoeven, D., J. R. Teijaro, and D. L. Farber. 2009. Pulse-oximetry accurately predicts lung pathology and the immune response during influenza infection. Virology 390:151-156.
5. Bingaman, A. W., D. S. Patke, V. R. Mane, M. Ahmadzadeh, M. Ndejembi, S. T. Bartlett, and D. L. Farber. 2005. Novel phenotypes and migratory properties distinguish memory CD4 T cell subsets in lymphoid and lung tissue. Eur J Immunol 35:3173-3186.