Craig Morita, MD, PhD
The Morita lab focuses on the study of human γδ T cells and nonpeptide antigens. γδ T cells function to bridge innate and adaptive immunity by recognizing nonpeptide, isoprenoid metabolites and by performing unique roles not played by αβ T cells. γδ T cells are very important in human microbial immunity as evidenced by the large expansions of Vγ2Vδ2 T cells that occur during many bacterial and parasitic infections. Once activated, γδ T cells kill most types of tumors. Clinical trials are in progress in many parts of the world to determine the role of Vγ2Vδ2 T cells in cancer immunotherapy.
We have found that human Vγ2V┊ T cells use their antigen receptors to recognize essential phosphorylated isoprenoid metabolites. Most bacteria and protozoan parasites use a different isoprenoid pathway than humans. Vγ2Vδ2 T cells recognize one of the intermediates in this pathway, termed HMBPP. They also recognize the self-metabolite, IPP, that 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 the antigen presenting molecule. We are also working to characterize a novel phosphoantigen produced by Staphylococcus aureus and other Gram-positive cocci (which use the mevalonate isoprenoid pathway and lack HMBPP), to identify the biochemical pathway responsible for the antigen's synthesis, and to determine the role of Vγ2Vδ2 T cells in immunity to Gram-positive cocci.
A second area of study has focused on Human γδ T cell Recognition of Nonpeptide Antigens: Discriminating Friend from Foe through the Recognition of Prenyl Pyrophosphate Metabolites. T cell subsets. We have found that Vγ2Vδ2 T cells can be divided into distinct memory subsets. These Vγ2Vδ2 subsets have different migratory and functional abilities. The different migratory abilities are due to differential expression of adhesion molecules and chemokine receptors. Our present studies focus on the factors that control the generation of memory Vγ2Vδ2 T cells and the importance of the different memory subsets in bacterial and tumor immunity. We are also studying IL-17A and IL-22 production by Vγ2Vδ2 T cells to determine the cytokines controlling their differentiation into Th17-like cells and the functional significance of this subset in human microbial immunity and autoimmunity.
A third area of study is to develop ©TM vaccines to prevent bacterial infections and for cancer immunotherapy. In clinical trials, stimulating Vγ2Vδ2 T cells has resulted in partial or complete remissions in some cancer patients with lymphoma, prostate cancer, and renal cell carcinoma. We are taking two approaches for vaccine development: engineering the metabolism of vaccine bacteria to make them overproduce HMBPP and synthesizing new lipophilic aminobisphosphonates. In preclinical studies, we are testing these ©TM vaccines in non-human primates and in immunodeficient mice transplanted with human blood cells.
- Cancer immunology
- Adaptive immunity
- Cell differentiation
- Pathogen recognition
- Immune cell activation and interactions
- Host-pathogen interactions
- T cell Biology
- Vaccines, Drugs, and Biologics
- Immune memory
- Human immunology