Megan A. Cooper, M.D., Ph.D.

Associate Professor
Pediatrics
Rheumatology
Pathology and Immunology

Immunology Program
Human and Statistical Genetics Program

Research Abstract:

Our laboratory investigates two areas of immunology, the biology of natural killer (NK) cells and immune defects in pediatric patients with immune dysregulation syndromes. First, we are interested in regulation of NK cell effector functions, including cytokine-induced NK cell memory. NK cells are innate immune lymphocytes capable of recognizing and killing target cells and producing immunoregulatory cytokines, especially interferon gamma IFN-y. We currently have several projects focused on metabolic regulation of NK cell function. We determined that NK cells have distinct metabolic requirements that are activation-dependent, and that glycolysis is essential for NK cell killing of infected cells during viral infection. We are currently using several novel in vivo genetic models to explore the role of metabolism on NK cell effector function during viral infection and in the context of anti-tumor responses.

A second area of interest is in using next-generation sequencing to identify genetic causes of inborn errors of immunity that present in children. We discovered a syndrome of early-onset autoimmunity caused by gain-of-function (GOF) mutations in STAT3. This collaborative study, led by my laboratory, demonstrated that the genetic variants in STAT3 lead to increased transcriptional activity of the encoded transcription factor, causing immune dysregulation. Current work on STAT3 in the laboratory is focused on using two mouse models we developed to investigate the mechanisms of autoimmunity in children with STAT3 GOF. We recently reported novel hemizygous variants in TLR8 associated with a new syndrome of neutropenia, lymphoproliferation, immune dysregulation, and bone marrow failure due to GOF in TLR8. Interestingly, 5 of 6 patients had mosaic variants, revealing a unique molecular mechanism for this new disorder. We have active projects investigating the mechanism of immune dysregulation in these patients.


Mentorship and Commitment to Diversity Statement:
The Cooper lab is committed to fostering a diverse and inclusive research environment for all trainees and staff. We appreciate that bringing together different voices is important for advancing science.

Selected Publications:

Aluri J, Bach A, Kaviany S, Chiquetto Paracatu L, Kitcharoensakkul M, Walkiewicz MA, Putnam CD, Shinawi M, Saucier N, Rizzi EM, Harmon MT, Keppel MP, Ritter M, Similuk M, Kulm E, Joyce M, de Jesus AA, Goldbach-Mansky R, Lee YS, Cella M, Kendall PL, Dinauer MC, Bednarski JJ, Bemrich-Stolz C, Canna SW, Abraham SM, Demczko MM, Powell J, Jones SM, Scurlock AM, De Ravin SS, Bleesing JJ, Connelly JA, Rao VK, Schuettpelz LG, Cooper MA. Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. Blood. 2021;137(18):2450-2462. PMCID:PMC8109013 PMID:33512449.https://pubmed.ncbi.nlm.nih.gov/33512449/

Mah-Som AY, Keppel MP, Tobin JM, Kolicheski A, Saucier N, Sexl V, French AR, Wagner JA, Fehniger TA, Cooper MA. Reliance on Cox10 and oxidative metabolism for antigen-specific NK cell expansion. Cell Rep. 2021;35(9):109209. PMCID:PMC8229496 PMID:34077722. https://pubmed.ncbi.nlm.nih.gov/34077722/

Wagner JA, Wong P, Schappe T, Berrien-Elliott MM, Cubitt C, Jaeger N, Lee M, Keppel CR, Marin ND, Foltz JA, Marsala L, Neal CC, Sullivan RP, Schneider SE, Keppel MP, Saucier N, Cooper MA, Fehniger TA. Stage-Specific Requirement for Eomes in Mature NK Cell Homeostasis and Cytotoxicity. Cell Rep. 2020;31(9):107720. https://pubmed.ncbi.nlm.nih.gov/32492428/

Mah AY, Rashidi A, Keppel MP, Saucier N, Moore EK, Alinger JB, Tripathy SK, Agarwal SK, Jeng EK, Wong HC, Miller JS, Fehniger TA, Mace EM, French AR, Cooper MA. Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control. JCI Insight. 2017;2(23): pii: 95128. doi: 10.1172/jci.insight.95128. https://pubmed.ncbi.nlm.nih.gov/29212951/ *Featured Immunology article in “JCI This Month”, January 2018, https://insight.jci.org/this-month/2018/1 

Lovric S, Goncalves S, Gee HY, Oskouian B, Srinivas H, Choi WI, Shril S, Ashraf S, Tan W, Rao J, Airik M, Schapiro D, Braun DA, Sadowski CE, Widmeier E, Jobst-Schwan T, Schmidt JM, Girik V, Capitani G, Suh JH, Lachaussée N, Arrondel C, Patat J, Gribouval O, Furlano M, Boyer O, Schmitt A, Vuiblet V, Hashmi S, Wilcken R, Bernier FP, Innes AM, Parboosingh JS, Lamont RE, Midgley JP, Wright N, Majewski J, Zenker M, Schaefer F, Kuss N, Greil J, Giese T, Schwarz K, Catheline V, Schanze D, Franke I, Sznajer Y, Truant AS, Adams B, Désir J, Biemann R, Pei Y, Ars E, Lloberas N, Madrid A, Dharnidharka VR, Connolly AM, Willing MC, Cooper MA, Lifton RP, Simons M, Riezman H, Antignac C, Saba JD, Hildebrandt F. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest. 2017;127(3):912-928. https://pubmed.ncbi.nlm.nih.gov/28165339/

Milner, J. D., Vogel, T. P., Forbes, L., Ma, C. A., Stray-Pedersen, A., Niemela, J. E., Lyons, J. J., Engelhardt, K. R., Zhang, Y., Topcagic, N., Roberson, E. D., Matthews, H., Verbsky, J. W., Dasu, T., Vargas-Hernandez, A., Varghese, N., McClain, K. L., Karam, L. B., Nahmod, K., Makedonas, G., Mace, E. M., Sorte, H. S., Perminow, G., Rao, V. K., O`Connell, M. P., Price, S., Su, H. C., Butrick, M., McElwee, J., Hughes, J., Willet, J., Swan, D., Xu, Y., Santibanez-Koref, M., Slowik, V., Dinwiddie, D. L., Ciaccio, C. E., Saunders, C. J., Septer, S., Kingsmore, S. F., White, A. J., Cant, A. J., Hambleton, S., Cooper, M. A. (2015). Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations. Blood, 125 (4), 591-599. https://pubmed.ncbi.nlm.nih.gov/25359994/

Keppel, M. P., Saucier, N., Mah, A. Y., Vogel, T. P., Cooper, M. A. (2015). Activation-Specific Metabolic Requirements for NK Cell IFN-γ Production. J Immunol, 194 (4), 1954-1962 PubMed: 25595780.

Tarbox JA, Keppel MP, Topcagic N, Mackin C, Ben Abdallah M, Baszis KW, White AJ, French AR, Cooper MA. Elevated double negative T cells in pediatric autoimmunity. Journal of Clinical Immunology, 34 (5):594-599, 2014. https://pubmed.ncbi.nlm.nih.gov/25595780/

Keppel MP, Yang L, Cooper MA. Murine NK cell intrinsic cytokine-induced memory-like responses are maintained following homeostatic proliferation. J. Immunol., 190 (9): 4754-4762, 2013. https://pubmed.ncbi.nlm.nih.gov/23530145/

Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, Cooper MA, Fehniger TA. Cytokine activation induces human memory-like NK cells. Blood, 120 (24): 4751-4760, 2012. PMID: 22983442.

Last Updated: 10/23/2021 5:10:46 PM

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