Biography

Influenza A virus (IAV) represents a global health concern, particularly for at risk segments of the population including the very young and aged. In the United States alone, seasonal IAV infection is responsible for over 200,000 hospitalizations per year and an economic burden estimated to exceed 87 billion dollars during the flu season. Protection against IAV generated through current vaccine strategies is not optimal; studies conducted during the 2014-2015 flu season estimated only around 25% efficacy of immunization across all age groups.

Most current vaccines aim to generate high titers of neutralizing antibodies that will recognize and bind to a specific pathogen thereby preventing infection. IAV vaccines target antibody production against the viral hemagglutinin (HA) and neuraminidase (NA) proteins that are key for facilitating entry into host cells and productive infection. However, IAV rapidly mutates to escape recognition by neutralizing antibodies and this largely underlies the need for annual vaccine reformulation, based on predictions of which HA and NA molecules will be expressed by seasonal IAV variants. Current vaccines against IAV are of very little protective efficacy in cases of mismatch between the HA and NA molecules present in the vaccine versus those expressed by circulating seasonal strains. Perhaps more importantly, current vaccines are ineffective when unexpected pandemic IAV strains, such as the ‘bird flu’ or ‘swine flu’, emerge during the flu season.

CD4 T cells, traditionally labeled as the ‘helper’ cells of the immune system, have recently been shown to also exert several powerful anti-viral functions. Evidence from animal models of IAV infection and clinical studies suggest that memory CD4 T cells can provide strong protection against several pathogens, including IAV, even in the absence of neutralizing antibody.

Dr. McKinstry’s lab is focused on two fundamental questions. First, how do memory CD4 T cells combat IAV? Our studies have identified that several specialized subsets of memory CD4 T cells contribute to viral clearance through unique mechanisms. Current research in the lab seeks to identify how to harness the anti-viral potential of memory CD4 T cells while minimizing immunopathology in the lung. Future work will determine whether protective memory CD4 T cell functions can be harnessed and optimized to combat other dangerous pathogens as well as cancers.

The second focus of Dr. McKinstry’s research is understanding how the most protective memory CD4 T cells are be generated through vaccination. Current vaccines do not stimulate the formation of strong T cell immunity. Recent studies have defined that memory T cells able to survive long-term at sites of infection (or vaccination) are crucial for providing optimal protection upon rechallenge. The requirements for generating such ‘tissue-resident’ memory T cells are not clear but seem to be distinct from the signals that drive the generation of memory cells present in secondary lymphoid organs. Defining critical elements of the pathway supporting tissue-resident memory CD4 T cell generation in the lung (the site of IAV infection) will allow for innovative vaccine strategies to improve protection against IAV and other important respiratory pathogens.

 

Publications: Peer-reviewed Journal Articles

Torrado, E., Fountain, J., Tighe, M., Reiley, W., Pearl, J., Zak, D., Thompson, E., Aderem, A., Solache, A., McKinstry, K.K., Strutt, T., Swain, S., and A. Cooper. Interleukin 27 regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection. Journal of Experimental Medicine, 212: 1449-63.

Sell. S., Guest, I., McKinstry, K.K., Strutt, T.M., Kohlmeier, J.E., Brincks, E., Tighe, M., Blackman, M.A.,Woodland, D.L., Dutton, R.W., and S.L. Swain. 2014. Intraepithelial T-cell cytotoxicity, induced bronchus associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza. Viral Immunology, 27:484-96.

McKinstry, K.K., Strutt, T.M., Bautista, B., Zhang, W., Kaung, Y., Cooper, A.M., and S.L. Swain. 2014. Effector CD4 T cell transition to memory requires late cognate interactions that induce autocrine IL-2. Nature Communications: 5:5377.

• corresponding author

Rudulier, C.D., McKinstry, K.K., Al-Yassin, G.A., Kroeger, D.R., and P. A. Bretscher. 2014. The number of responding CD4 T cells and the dose of antigen conjointly determine the Th1/Th2 phenotype by modulating B7/CD28 interactions. Journal of Immunology, 192: 5140-50.

Jain, N., Miu, B., Jiang, J., McKinstry, K.K., Prince, A., Swain, S.L., Greiner, D., Thomas, C.J., Sanderson, M.J., Berg, L.J., and J. Kang. 2013. CD28 and ITK signals regulate autoreactive T cell trafficking. Nature Medicine, 19: 1632-37.

Strutt, T.M., McKinstry, K.K., Marshall, N.B., Vong, A.M., Dutton, R.W., and S.L. Swain. 2013. Multipronged CD4 T cell effector and memory responses cooperate to provide potent immunity against respiratory viruses. Immunological Reviews, 255: 149-64. (invited review)

McKinstry, K.K., Dutton, R.W., Swain, S.L., and T. M. Strutt. 2013. Memory CD4 T cell-mediated immunity against influenza A virus: more than a little helpful. Archivum Immunologiae et Therapiae Experimentalis, 61: 341-53. (invited review)

• corresponding author

Hamada, H., Bassity, E., Flies, A., Strutt, T.M., de Luz Garcia-Hernandez, M., McKinstry, K.K., Zou, T., Swain, S.L., and R.W. Dutton. 2013. Multiple redundant effector mechanisms of CD8⁺ T cells protect against influenza infection. Journal of Immunology, 190: 296-306.

Strutt, T.M., McKinstry, K.K., Kaung, Y., Bradley, L.M., and S.L. Swain. 2012. Memory CD4⁺ T cell-mediated protection depends on secondary effectors that are distinct from and superior to primary effectors. Proceedings of the National Academy of Sciences (USA), 109: E2551-60.

• co-first author
• corresponding author

McKinstry K.K., Strutt, T.M., Kaung, Y., Brown, D.M., Sell, S., Dutton, R.W., and S.L. Swain. 2012. Memory CD4⁺ T-cells protect against influenza by multiple synergizing mechanisms. Journal of Clinical Investigation, 122: 847-56.

• corresponding author
• featured commentary in Journal of Clinical Investigation
• featured as a Research Highlight in Nature Reviews Immunology

Swain, S.L., McKinstry, K.K., and T. M. Strutt. 2012. Expanding roles for CD4⁺ T cells in immunity to viruses. Nature Reviews Immunology, 12: 136-48. (invited review)

McKinstry, K.K., Strutt, T.M., and S.L. Swain. 2011. Hallmarks of CD4 T cell immunity against influenza. Journal of Internal Medicine, 269: 507-518. (invited review)

• corresponding author

McKinstry, K.K., Strutt, T.M., and S.L. Swain. 2010. Regulation of CD4 T cell contraction during pathogen challenge. Immunological Reviews, 236: 110-24. (invited review)

Strutt, T.M., McKinstry, K.K., Dibble, J.P., Winchell, C., Kuang, Y., Curtis, J.D., Huston, G., Dutton, R.W., and S.L. Swain. 2010. Memory CD4 T cells induce innate responses independent of pathogen. Nature Medicine, 16: 558-64.

• co-first author
• selected and reviewed by Faculty of 1000
• featured as a Research Highlight in Nature Reviews Immunology

McKinstry, K.K., Strutt, T.M., and S.L. Swain. 2010. The potential of CD4 T cell memory. Immunology, 130: 1-9. (invited review)

• corresponding author

McKinstry, K.K., Strutt, T.M., Buck, A., Curtis, J.D., Dibble, J.P., Huston, G., Tighe, M., Hamada, H., Sell, S., Dutton, R.W., and S.L. Swain. 2009. IL-10 deficiency unleashes an influenza-specific Th17 response and enhances survival against high dose challenge. Journal of Immunology, 182: 7353-63.

• corresponding author
• selected and reviewed by Faculty of 1000

Hamada H, Garcia-Hernandez L., Reome, J.B., Misra, S.K., Strutt, T.M., McKinstry, K.K., Cooper, A.M., Swain, S.L., and R.W. Dutton. 2009. Tc17, a unique subset of CD8 T cells that can protect against lethal influenza challenge. Journal of Immunology 182: 3469-81.

Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2009. Functionally diverse subsets in CD4 T cell responses against influenza. Journal of Clinical Immunology 29: 145-50. (invited review)

Jelley-Gibbs, D.M., Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2008. Influencing the fates of CD4 T cells on the path to memory: lessons from influenza. Immunology and Cell Biology 86: 343-52. (invited review)

McKinstry, K.K., Strutt, T.M., and S.L. Swain. 2008. The effector to memory transition of CD4 T cells. Immunologic Research 40: 114-27. (invited review)

• corresponding author

McKinstry, K.K., Golech, S., Lee, W.H., Huston, G., Weng, N.P., and S.L. Swain. 2007. Rapid default transition of CD4 T cell effectors to functional memory cells. Journal of Experimental Medicine 204: 2199-211.

• corresponding author

Li, X., McKinstry, K.K., Swain, S.L., and D.K. Dalton. 2007. IFN-gamma acts directly on activated CD4+ T cells during mycobacterial infection to promote apoptosis by inducing components of the intracellular apoptosis machinery and by inducing extracellular proapoptotic signals. Journal of Immunology 179: 939-49.

Jelley-Gibbs, D.M., Dibble, J.P., Brown, D.M., Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2007. Persistent depots of influenza antigen fail to induce a cytotoxic CD8 T cell response. Journal of Immunology 178: 7563-70.

Swain, S.L., Agrewala, J.N., Brown, D.M., Jelley-Gibbs, D.M., Golech, S., Huston, G., Jones, S.C, Kamperschroer, C., Lee, W-H., McKinstry, K.K., Roman, E., Strutt, T. and N. Weng. 2006. CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza. Immunological Reviews 211: 8-22. (invited review)

Strutt, T., Uzonna, J., McKinstry, K.K., and P. Bretscher. 2006. Activation of thymic T cells by MHC alloantigen requires syngeneic, activated CD4+ T cells and B cells as APC. International Immunology 18: 719-28.

 

Publications: Book Chapters

S.L. Swain, Strutt, T.M., and K.K. McKinstry. 2015.  Immunity to Viral Infection: CD4 T Cell Immunity to Viral Infection. In Encyclopedia of Immunobiology. Ed. Christine Biron.  Chapter 14026 (Accepted).

McKinstry K.K., and Strutt T.M. 2014. Regulation and Maintenance of Adaptive Immunity. In Pathobiology of Human Disease. Ed. Linda M. McManus and Richard N. Mitchell, p. 20-35.

Strutt, T.M., McKinstry, K.K., and S.L. Swain. 2011. Control of innate immunity by memory CD4 T cells. In 3^rd Crossroads between Innate and Adaptive Immunity. Ed. B. Pulendran, S. Schoenberger, and P. Katsikis, p 57-68.

McKinstry, K., Ismail, N., Peters, N., Strutt, T. and P. Bretscher. 2005. Non-interference, independence and coherence of immune responses: Implications for macroimmunology and strategies of intervention. In Altered Immunoregulation and Human Disease. Ed. Reginald M. Gorczynski, p 93-113.