Over 36 million people are living with human immunodeficiency virus (HIV), and HIV continues to infect over one million new people every year. Only 50% of infected individuals are accessing antiretroviral therapy, and those with uncontrolled HIV infection are highly susceptible to co-infections with other pathogens like Mycobacterium tuberculosis (Mtb). I am interested in the development of vaccines and immunotherapies for HIV and Mtb. Specifically, my work focuses on harnessing unconventional T cells as vaccine targets and immunotherapies including Mucosal associated invariant T cells (MAITs) and major histocompatibility complex (MHC)-E restricted T cells.
MAITs recognize bacterial, fungal, and yeast derived riboflavin metabolites on the surface of infected cells in the context of major histocompatibility (MHC) related protein 1 (MR1). MR1 is conserved amongst the human population; thus, MAITs provide a potential universal Mtb vaccine or therapeutic agent. MAITs can rapidly exert their effector function to prevent further dissemination of pathogens. Many questions regarding MAIT biology remain unanswered including:
- Can we selectively expand MAITs with the appropriate stimulus, and will this lead to better pathogen control?
- Do MAITs exhibit the critical features of T cell memory required for a vaccine (ie, will they respond more rapidly and in greater number upon re-exposure to the same pathogen)?
- Do MAITs contribute to auto-immune diseases like colitis and irritable bowel syndrome and are these potential side-effects of vaccine-induced MAIT expansion?
- Can MAITs be expanded ex vivo for use in adoptive immunotherapies?
These questions are critical to understanding whether MAITs are an appropriate target for a Mtb vaccine or immunotherapy and are a focus of my research.
MHC-E Restricted T cells
MHC-E serves as a flag on the cell surface indicating normal antigen processing and presentation by providing an inhibitory signal to natural killer (NK) cells. In the absence of MHC-E, NK cells respond by killing the affected cell. Because cancers and other pathogens often subvert antigen processing and presentation to avoid detection, MHC-E signaling provides an additional safety measure against tumors and infection. Recently, studies have demonstrated that MHC-E can also present pathogen derived peptides to CD8+ T cells. In addition, like MR1, MHC-E exhibits very limited genetic diversity amongst the human population; thus, MHC-E restricted T cells are a high priority target for development of universal vaccines. Work in the lab focuses on eliciting MHC-E restricted T cells and their biology.
Dr. Greene graduated from the University of Wisconsin –Madison in 2005 with a B.S. in Genetics. He received his Ph.D. from the Department of Cellular and Molecular Pathology at the University of Wisconsin –Madison in 2010 with Dr. David O'Connor. He continued working as an Assistant and then Associate Scientist until 2015 when he joined Dr. Jonah Sacha's laboratory at the Vaccine &Gene Therapy Institute as a Staff Scientist. He was promoted to Research Assistant Professor in 2018.
- Walters LC, Harlos K, Brackenridge S, Rozbesky D, Barrett JR, Jain V, Walter TS, O'Callaghan CA, Borrow P, Toebes M, Hansen SG, Sacha J, Abdulhaqq S, Greene JM, Früh K, Marshall E, Picker LJ, Jones EY, McMichael AJ, Gillespie GM. Pathogen-derived HLA-E bound epitopes reveal broad primary anchor pocket tolerability and conformationally malleable peptide binding. Nat Comms. Nature Publishing Group;2018 Aug 7;9(1):3137. PMCID: PMC6081459
- Wu HL, Wiseman RW, Hughes CM, Webb GM, Abdulhaqq SA, Bimber BN, Hammond KB, Reed JS, Gao L, Burwitz BJ, Greene JM, Ferrer F, Legasse AW, Axthelm MK, Park BS, Brackenridge S, Maness NJ, McMichael AJ, Picker LJ, O'Connor DH, Hansen SG, Sacha JB. The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques. J. Immunol. American Association of Immunologists;2017 Nov 17;:ji1700841. PMCID: PMC5736429
- Greene JM, Dash P, Roy S, McMurtrey C, Awad W, Reed JS, Hammond KB, Abdulhaqq S, Wu HL, Burwitz BJ, Roth BF, Morrow DW, Ford JC, Xu G, Bae JY, Crank H, Legasse AW, Dang TH, Greenaway HY, Kurniawan M, Gold MC, Harriff MJ, Lewinsohn DA, Park BS, Axthelm MK, Stanton JJ, Hansen SG, Picker LJ, Venturi V, Hildebrand W, Thomas PG, Lewinsohn DM, Adams EJ, Sacha JB. MR1-restricted mucosal-associated invariant T (MAIT) cells respond to mycobacterial vaccination and infection in nonhuman primates. Mucosal Immunol. 2016 Oct 19;10(3):802–13. PMCID: PMC5397382
- Mohns MS, Greene JM, Cain BT, Pham NH, Gostick E, Price DA, O'Connor DH. Expansion of Simian Immunodeficiency Virus (SIV)-Specific CD8 T Cell Lines from SIV-Naive Mauritian Cynomolgus Macaques for Adoptive Transfer. Silvestri G, editor. J. Virol. 2015 Sep 1;89(19):9748–57. PMCID: PMC4577914
- Greene JM, Lhost JJ, Hines PJ, Scarlotta M, Harris M, Burwitz BJ, Budde ML, Dudley DM, Pham N, Cain B, Mac Nair CE, Weiker MK, O'Connor SL, Friedrich TC, O'Connor DH. Adoptive Transfer of Lymphocytes Isolated from Simian Immunodeficiency Virus SIVmac239 nef-Vaccinated Macaques Does Not Affect Acute-Phase Viral Loads but May Reduce Chronic-Phase Viral Loads in Major Histocompatibility Complex-Matched Recipients. J. Virol. 2013 Jun 10;87(13):7382–92. PMCID: PMC3700297
- Rout N, Greene J, Yue S, O'Connor D, Johnson RP, Else JG, Exley MA, Kaur A. Loss of Effector and Anti-Inflammatory Natural Killer T Lymphocyte Function in Pathogenic Simian Immunodeficiency Virus Infection. Douek DC, editor. PLoS Pathog. 2012 Sep 20;8(9):e1002928. PMCID: PMC3447755
- Greene JM, Lhost JJ, Burwitz BJ, Budde ML, MacNair CE, Weiker MK, Gostick E, Friedrich TC, Broman KW, Price DA, O'Connor SL, O'Connor DH. Extralymphoid CD8+ T Cells Resident in Tissue from Simian Immunodeficiency Virus SIVmac239 nef-Vaccinated Macaques Suppress SIVmac239 Replication Ex Vivo. J. Virol. 2010 Mar 8;84(7):3362–72. PMCID: PMC2838091