Award Abstract # 2103367
The Third Domain of T cells: the biology of gamma mu T cells in non-eutherian mammals

NSF Org: IOS
Division Of Integrative Organismal Systems
Recipient: UNIVERSITY OF NEW MEXICO
Initial Amendment Date: July 2, 2021
Latest Amendment Date: July 2, 2021
Award Number: 2103367
Award Instrument: Standard Grant
Program Manager: Joanna Shisler
jshisler@nsf.gov
 (703)292-5368
IOS
 Division Of Integrative Organismal Systems
BIO
 Directorate for Biological Sciences
Start Date: August 1, 2021
End Date: July 31, 2026 (Estimated)
Total Intended Award Amount: $687,031.00
Total Awarded Amount to Date: $687,031.00
Funds Obligated to Date: FY 2021 = $687,031.00
History of Investigator:
  • Robert Miller (Principal Investigator)
    rdmiller@unm.edu
Recipient Sponsored Research Office: University of New Mexico
1 UNIVERSITY OF NEW MEXICO
ALBUQUERQUE
NM  US  87131-0001
(505)277-4186
Sponsor Congressional District: 01
Primary Place of Performance: University of New Mexico
1700 Lomas Blvd. NE, Suite 2200
Albuquerque
NM  US  87131-0001
Primary Place of Performance
Congressional District:
01
Unique Entity Identifier (UEI): F6XLTRUQJEN4
Parent UEI:
NSF Program(s): Symbiosis Infection & Immunity
Primary Program Source: 01002122DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 9178, 9179, 9251
Program Element Code(s): 765600
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.074

ABSTRACT

T cells are a critical immune cell type in all vertebrate animals. T cell deficiencies lead to susceptibility to pathogens and increased cancer rates. There are a variety of T cell types and subtypes. Their presence and function can vary considerably across between distantly related species. This project investigates a new T cell, called the ??T cell, that was discovered in a model marsupial, the gray short-tailed opossum. ??T cells are found in marsupials and monotremes like the duckbill platypus. ??T cells, therefore, are ancient and present in the ancestors of all mammals, but for unknown reasons was lost in the placental mammals such as humans. Understanding why they were lost from the placental mammals requires understanding their function in species that still have ??T cells. This project investigates the development, distribution, and patterns of gene expression of ??T cells to gain insights into their function. This project will investigate the function of a novel receptor protein, called TCR?, that defines the ?? T cell. TCR? shares structural similarity to an antibody type called nanobodies. Nanobodies are useful diagnostic and therapeutic tools. If TCR? has the properties of nanobodies it raises the potential for generating these tools in a species easily maintained in standard laboratory animal facilities. This project will provide research experiences for undergraduates transferring from two-year Community College to a four-year, Research-intensive University. Doctoral students on the project will work directly with these undergraduates to gain mentoring experience and enhance their own career skills.


This project investigates the development, distribution, and phenotype of a novel type of T cells, the ?? T cell. All studies will be performed using a model marsupial, the gray short-tailed opossum. ?? T cell function remains unknown and preliminary results support a limited time during postnatal development when they are generated in the thymus, have a limited tissue distribution, and a limited T cell receptor (TCR) repertoire in the adult animal. Using combinations of reverse-transcriptase PCR and single-cell RNA sequencing this project will investigate: 1) the timing and the progression of the ?? T cell developmental stages, 2) the tissue distribution throughout maturation and in the adults along with tissue specific phenotyping at the single cell level, and 3) lastly, investigate if there is an association between the diversity of ??TCR and tissue localization. In addition, this project will use phage display technology to investigate the nature of antigen binding by the ??TCR. Specifically, mRNA isolated from spleens of immunized opossums will be used to create libraries of the putative antigen binding domain of ??TCR using a phage display vector. Clones capable of binding the immunizing antigens will be selected by rounds of panning and characterized further by sequencing to identify the clones that are antigen specific. Once clones are identified these will be used to identify the single cells to associate phenotype with antigen specificity. It is anticipated that these results will provide the basis for testable hypotheses on the function or functions of ?? T cells.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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Morrissey, K A and Stammnitz, M R and Murchison, E and Miller, R D "Comparative genomics of the T cell receptor locus in marsupials and monotremes" Immunogenetics , v.75 , 2023 https://doi.org/10.1007/s00251-023-01320-w Citation Details
Morrissey, Kimberly_A and Sampson, Jordan_M and Rivera, Megan and Bu, Lijing and Hansen, Victoria_L and Gemmell, Neil_J and Gardner, Michael_G and Bertozzi, Terry and Miller, Robert_D "Comparison of Reptilian Genomes Reveals Deletions Associated with the Natural Loss of T Cells in Squamates" The Journal of Immunology , v.208 , 2022 https://doi.org/10.4049/jimmunol.2101158 Citation Details
Sampson, Jordan M and Morrissey, Kimberly A and Douek, Daniel C and Miller, Robert D "A family of olfactory receptors uniquely expanded in marsupial and monotreme genomes are expressed by a T cell subset also unique to marsupials and monotremes" Developmental & Comparative Immunology , v.154 , 2024 https://doi.org/10.1016/j.dci.2024.105149 Citation Details

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