Respiratory tract infections can have significant health impacts and are amongst the leading causes of death worldwide. Our best defense against respiratory infection is vaccination. Vaccination induced protection against infection is mediated by immunological memory, and CD4 T cells are key orchestrators of these responses. The majority of immunological memory studies to date have focused on the differentiation, survival, and delineation of the anti-pathogen defense mechanisms employed by pathogen-specific T cells. It has become increasingly clear over the last decade that many different subsets of CD4 T helper cells can be generated during immune responses and these each perform unique functions. Herein, a previously unappreciated role of a potentially novel subset of memory CD4 T cells will be established.
The specific aims of this proposal are centered upon the hypothesis that memory CD4 T cells, such as those induced by vaccination, figure prominently in the orchestration and maintenance of tissue homeostasis. A focus of this research will be to determine whether pathogen specific memory CD4 T cells, in addition to orchestrating and mediating beneficial anti-pathogen defense functions, also function to hasten wound repair through the increased mobilization of innate lymphoid cells during the early phases of the immune response to respiratory virus infection. Protective CD4 T cell immune responses against Influenza A virus will be used as a highly relevant model of vaccination induced memory. Influenza A virus causes a potentially lethal respiratory infection that despite current vaccination efforts remains a serious public health concern. Furthermore, innate lymphoid cells have recently been shown to play key roles in tissue reparative processes during the resolution phase of influenza A virus infection. In the first aim, the dynamics of innate lymphoid cell responses during CD4 T cell recall responses, and potential mechanisms underlying how they are mobilized will be interrogated. In the second aim, whether memory CD4 T cells differentially activate innate lymphoid cells to have enhanced reparative capacity will be explored. The insight gained from the proposed studies will advance our ability to develop improved vaccines that elicit both memory CD4 T cells capable of orchestrating protective anti- pathogen defenses as well as those capable of orchestrating tissue homeostasis. This research may also lead to the development of therapeutic strategies to advance wound healing in tissues damaged by injury or trauma and thus has incredibly broad implications for improving human health.

Public Health Relevance

Our current understanding of protective immunity is that adaptive immune cells, generated through vaccination or previous infection, prevent subsequent illness with the same pathogen through more rapid and robust pathogen-specific defense responses. This research project will provide insight into a completely novel function of protective immunity in preventing and repairing tissue damage caused by infection. Arguably, this may be the most important function of a specific group of immune cells, CD4 T helper cells, during protective immune responses against pathogens. The insight gained from the proposed studies will advance our ability to develop improved vaccines and may also lead to the development of therapeutic strategies to advance wound healing.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
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Immunity and Host Defense Study Section (IHD)
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Kelly, Halonna R
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University of Central Florida
Other Basic Sciences
Schools of Medicine
United States
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Strutt, Tara M; McKinstry, Karl Kai; Kuang, Yi et al. (2016) Direct IL-6 Signals Maximize Protective Secondary CD4 T Cell Responses against Influenza. J Immunol 197:3260-3270