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A role of lysophosphatidylcholine transporter MFSD2A in CD8+T cell memory and secondary response to infection

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 (Unpublished)

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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Status: Unpublished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:
CreatorsEmailPitt UsernameORCID
Piccirillo, Annpiccirilloann@gmail.comANP1000000-0001-7464-9222
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairD'Cruz, Louiseldcruz@pitt.eduldcruz
Committee MemberPadiath, Quasarqpadiath@pitt.eduqpadiath
Committee MemberDemirci, F. Yesimfyd1@pitt.edufyd1
Committee MemberHawse, WilliamWHAWSE@pitt.eduwhawse
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: Graduate 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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