Department of Internal Medicine
Craig T. Morita, M.D., Ph.D.
Coordinator, Rheumatology Fellowship Program
My lab focuses on the study of human γδ T cells and nonpeptide antigens. γδ T cells are a distinct subset of T cells that function to bridge innate and adaptive immunity by recognizing nonpeptide, isoprenoid metabolites and by performing unique roles not played by αβ T cells. Pathogen recognition by human γδ T cells is very important in microbial immunity as evidenced by the large expansions of Vγ2Vδ2 T cells (up to 1 in 2 circulating T cells) that occur during many bacterial and parasitic infections. Moreover, once activated, Vγ2Vδ2 T cells kill most types of tumors by recognizing them using the NK receptors that they express. Thus, efforts are ongoing to determine how to use Vγ2Vδ2 T cells for cancer immunotherapy.
We have found that human γδ T cells use their Vγ2Vδ2 antigen receptors to recognize essential phosphorylated metabolites in isoprenoid biosynthesis. Bacteria and protozoan parasites use a distinct metabolic pathway to make isoprenoids. Vγ2Vδ2 T cells recognize one of the intermediates in this pathway, termed HMBPP. They also recognize the self-metabolite, IPP, which accumulates in cells after aminobisphosphonate drug treatment. One area of focus of the lab is to determine how these small phosphoantigens are presented to Vγ2Vδ2 T cells by identifying its novel antigen presenting molecule. We are also working to identify a novel bacterial antigen produced by Staphylococcus aureus and to determine the role of Vγ2Vδ2 T cells in immunity to Gram-positive cocci.
A second area of study has focused on the development of memory in γδ T cells. We find that distinct memory subsets of Vγ2Vδ2 T cells exist. These Vγ2Vδ2 subsets have different migratory and functional abilities. The different migration is due to differential expression of adhesion molecules and chemokine receptors that determine the homing capabilities of cells. Our present studies focus on the factors that control the generation of memory Vγ2Vδ2 T cells and the relative importance of the different memory subsets in bacterial and tumor immunity.
A third area of study is to develop γδ vaccines for bacterial infections and for cancer immunotherapy. In clinical trials, stimulating Vγ2Vδ2 T cells has resulted in partial and complete remissions in some cancer patients with lymphoma, prostate cancer, and renal cell carcinoma. We are testing new lipophilic bisphosphonates as vaccines for γδ T cells. We are also engineering the metabolism of vaccine bacteria to make them overproduce the HMBPP antigen. In preclinical studies, we are testing these different vaccines in monkeys and in immunodeficient mice transplanted with human blood cells.
Specific Areas of Interest
- Antigen Recognition by γδ T Cells
- Identification of a Novel Phosphoantigen Recognized by γδT Cells
- T Cell-mediated Immunity to Infection
- Generation and Differentiation of Memory γδT Cell Subsets
- IL-17A- and IL-22-producing human γδT Cells
- Cancer Immunotherapy with γδT Cells
Links of Interest
Honors, Awards, and Organizations
- Phi Beta Kappa
- Dean's Prize in Student Research, U.C.S.F. School of Medicine
- Medical Scientist Training Program Fellowship
- Arthritis Foundation Fellowship Award
- Leukemia Society Special Fellowship
- American College of Rheumatology/Arthritis Foundation Investigator Award
- Howard Hughes Medical Institute Research Resources Award
- American College of Rheumatology/Arthritis Foundation Biomedical Science Award
- Arthritis Foundation Former Fellow "Hero" Award
- 2007 International Immunology Outstanding Merit Award
- American Association of Immunologists
- American College of Rheumatology
- American Society for Microbiology
- Central Society for Clinical Research
- Diplomate, American Board of Internal Medicine and Board of Rheumatology
- Tanaka Y, Morita CT, Tanaka Y, Nieves E, Brenner MB, Bloom BR. Natural and synthetic non-peptide antigens recognized by humanγδ T cells. Nature 1995; 375:155.
- Morita CT, Beckman EM, Bukowski JF, Tanaka Y, Band H., Bloom BR, Golan, DE, Brenner MB. Direct presentation of nonpeptide prenyl pyrophosphate antigens to humanγδ T cells. Immunity 1995; 3:495.
- Tanaka Y, Sano S, Nieves E, De Libero G, Rosa D, Modlin RL, Brenner MB, Bloom BR, Morita CT. Nonpeptide ligands for humanγδ T cells. Proc Natl Acad Sci USA 1994; 91:8175.
- Bukowski JF, Morita CT, Brenner MB. Human γδT cells recognize alkylamines derived from tea, edible plants, and microbes: implications for innate immunity. Immunity 1999; 11:57.
- Morita CT, Li H, Lamphear JG, Rich RR, Fraser JD, Mariuzza RA, Lee HK. Superantigen recognition by γδ T cells: SEA recognition site for human Vγ2 T cell receptors. Immunity 2001; 14:331.
- Puan K-J, Jin C, Wang H, Sarikonda G, Raker AM, Lee HK, Samuelson MI, Märker-Hermann E, Pasa-Tolic L, Kolas-Nieves E, Giner J-L, Kuzuyama T, Morita CT. Preferential recognition of a microbial metabolite by human Vγ2Vδ2 T cells. Int Imm 2007; 19:657.
- Zhang Y, Yin F, Cao R, Lin F-Y, Wang H, Krysiak K, Mukkamala D, Morita CT*, Oldfield E*. Lipophilic, pyridinium bisphosphonates are potentγδT cell activators. Angew Chem Int Ed Engl 2010; 49: 1136.
- Wang H, Fang Z, Morita CT. Vγ2Vδ2 T cell receptor recognition of prenyl pyrophosphates is dependent on all CDRs. J Immunol 2010; 184:6209.
- Ness-Schwickerath, K, Jin C, Morita CT. Cytokine requirements for the differentiation and expansion of IL-17A- and IL-22-producing human Vγ2Vδ2 T cells. J Immunol 2010; 184:7268.
- Morita CT, Mariuzza, RA, Brenner, MB. Antigen recognition by human γδ T cells: pattern recognition by the adaptive immune system. Springer Sem Immunopath 2000; 22:191.
- Morita CT, Jin C, Sarikonda G, Wang H. Nonpeptide antigens, presentation mechanisms, and immunological memory of human Vγ2Vδ2 T cells: discriminating friend from foe through the recognition of prenyl pyrophosphate antigens. Immunol Rev 2007; 215:59.
- Ness-Schwickerath K, Morita CT. Regulation and function of IL-17- and IL-22-producing γδ T cells. CMSL 2011; in press.