UMMS Affiliation

Department of Pathology; Graduate School of Biomedical Sciences, Program in Immunology and Microbiology

Publication Date


Document Type



Immunology of Infectious Disease | Immunopathology | Immunoprophylaxis and Therapy | Influenza Virus Vaccines | Virology | Virus Diseases


Influenza viral evolution presents a formidable challenge to vaccination due to the virus' ability to rapidly mutate to evade immune responses. Live influenza infections generate large and diverse CD4 effector T cell responses that yield highly protective, long-lasting CD4 T cell memory that can target conserved viral epitopes. We review advances in our understanding of mechanisms involved in generating CD4 T cell responses against the influenza A virus (IAV), focusing on specialized follicular helper (TFH) and CD4 cytotoxic (ThCTL) effector subsets and on CD4 T cell memory. We also discuss two recent findings in context of enhancing vaccine responses. First, helper T cells require priming with APC secreting high levels of IL-6. Second, the transition of IAV-generated effectors to memory depends on IL-2, costimulation and antigen signals, just before effectors reach peak numbers, defined as the "memory checkpoint." The need for these signals during the checkpoint could explain why many current influenza vaccines are poorly effective and elicit poor cellular immunity. We suggest that CD4 memory generation can be enhanced by re-vaccinating at this time. Our best hope lies in a universal vaccine that will not need to be formulated yearly against seasonal antigenically novel influenza strains and will also be protective against a pandemic strain. We suggest a vaccine approach that elicits a powerful T cell response, by initially inducing high levels of APC activation and later providing antigen at the memory checkpoint, may take us a step closer to such a universal influenza vaccine.


CD4 T cells, cell-mediated immunity, influenza, late-antigen, memory checkpoint, vaccination

DOI of Published Version



Front Immunol. 2016 Apr 11;7:136. doi: 10.3389/fimmu.2016.00136. eCollection 2016. Link to article on publisher's site

Journal/Book/Conference Title

Frontiers in immunology

Related Resources

Link to Article in PubMed

PubMed ID


Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.