Piccirillo, Ann
(2019)
A role of lysophosphatidylcholine transporter MFSD2A in CD8+T cell memory and secondary response to infection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Immunometabolism is fueling breakthroughs across oncology, infection control, and inflammation research. It is appreciated that CD8 T cells are important players in all of the above mentioned fields. Access to metabolic nutrients is critical for an effective CD8 T cell immune response to infection. Other groups have successfully identified transporters for exogenous import of sugars and amino acids for CD8 T cells, however, there is still a knowledge gap for how CD8 T cells can actively transport exogenous fatty acids. Here, I propose the lysophosphatidylcholine (LPC) transporter, Major Facilitator Super Family Domain Containing 2a (MFSD2A), is upregulated on activated CD8 T cells and is essential for memory T cell maintenance. MFSD2A deficiency in mice resulted in decreased import of LPC esterified to long chain fatty acids (LCFAs) into activated CD8 T cells, reduced memory T cell formation and maintenance, and reduced response to secondary infection. Import of LPCs was required to maintain T cell homeostatic turnover, that when lost resulted in a decreased memory T cell pool and therefore a reduced secondary response to secondary infection. I hypothesize that de novo fatty acid synthesis (FAS) is upregulated to compensate for loss of MFSD2A. These data were determined by using a thorough and multidisciplinary approach that combines the fields of immunology and human genetics. Importantly, there are families with known mutations in MFSD2A. These families have not been immunophenotyped for CD8 T cell dysregulation due to loss of MFSD2A, but it is reasonable to suggest that they may suffer from a decreased response to infection. This project is relevant to public health because there is currently a knowledge gap in how exogenous lipid species imported by MFSD2A can affect the CD8 T cell immune response to infection, including how MFSD2A and LPC deliverables could be used for future immunotherapy targets.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
30 January 2019 |
| Date Type: |
Publication |
| Defense Date: |
30 October 2018 |
| Approval Date: |
30 January 2019 |
| Submission Date: |
27 November 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
118 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Human Genetics |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
MFSD2A, LPC, T Cells, CD8 T cells, lipids, lipid metabolism, T cell metabolism, immunometabolism, immunology |
| Date Deposited: |
30 Jan 2019 18:48 |
| Last Modified: |
30 Jan 2019 18:48 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/35612 |
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