CD8 T cells are critical constituents of the cell-mediated branch of the adaptive immune response, whose extensive study has revealed life cycle phases from naive surveillance to effector expansion, effector contraction, and ultimately memory maintenance. The molecular processes that regulate each of these phases are of great interest and are now beginning to be understood. One area of specific interest is the regulation of cellular metabolism as T cells transition from anabolism during expansion to catabolic restrictions during contraction. During the current funding period, we have found that CD8 T cells lacking the adapter protein TRAF6 mount a normal primary response to bacterial infection, but then undergo hyper-contraction, resulting in profoundly deficient T cell memory. Intriguingly, we were able to link this defect to a previously unrecognized requirement for induction of metabolic fatty acid oxidation (FAO). Therefore, in this competing renewal application, we propose to further examine the link(s) between TRAF6, FAO, and CD8 T cell memory, and to determine whether, and in what way, these relationships are shaped by external factors encountered by T cells during immune responses. We will do so by pursuing two broad specific aims: (1) Characterize the relationship between TRAF6, FAO, and CD8 T cell memory: We propose examining further the effect of TRAF6 deficiency on memory development and maintenance by employing models which allow for temporally-modulated deletion of TRAF6. We will also dissect the relationship balancing FAO induction per se against broader regulation of cell survival during contraction. Having indirectly linked FAO and memory via TRAF6, we now propose to determine whether specific, genetically targeted, enhancement of FAO positively affects memory formation in otherwise normal cells and/or rescues memory in TRAF6-deficient cells. (2) Assess the effects of extrinsic factors on TRAF6-dependent FAO induction and CD8 T memory: Our preliminary data suggest that TRAF6-deficient CD8 T cells possess differential capacity to develop memory in response to a model bacterial versus viral infection, and remarkably, that treatment with the virus-associated TLR ligand Poly I:C can (at least partially) rescue the TRAF6-associated CD8 T cell memory defect. Because of the relationship we have uncovered between TRAF6, CD8 T cell memory, and FAO, we will examine how external (e.g., Poly I:C and the closely associated cytokine Type I IFN) and internal (i.e., FAO) T cell memory-related factors reach a molecular intersection at TRAF6. This final component will be probed through complementary bioinformatic and biochemical approaches. All together, the studies proposed herein should greatly improve contextualization of our exciting finding that TRAF6 and metabolism are linked in a manner critical to CD8 T memory formation, and should provide significant advances in our understanding of the cell-intrinsic processes that drive memory cell development in response to different types of infections, findings of potentially considerable value to future vaccine design.

Public Health Relevance

Proper immune responses are necessary to control pathogenic infections. It is equally important to limit immunological responses so that they do not cause chronic inflammation or autoimmune diseases. As such, understanding the molecular and cellular pathways that control immune responses is a critical step to forming a foundation for novel intervention strategies to treat various chronic infectious or inflammatory diseases.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Kelly, Halonna R
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University of Pennsylvania
Schools of Medicine
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Walsh, Matthew C; Takegahara, Noriko; Kim, Hyunsoo et al. (2018) Updating osteoimmunology: regulation of bone cells by innate and adaptive immunity. Nat Rev Rheumatol 14:146-156
Han, Daehee; Walsh, Matthew C; Kim, Kwang Soon et al. (2017) Dendritic cell expression of the signaling molecule TRAF6 is required for immune tolerance in the lung. Int Immunol 29:71-78
Lin, Jiqiang; Yang, Lu; Silva, Hernandez Moura et al. (2016) Increased generation of Foxp3(+) regulatory T cells by manipulating antigen presentation in the thymus. Nat Commun 7:10562
Park, Eui-Soon; Choi, Seunga; Shin, Bongjin et al. (2015) Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction. J Biol Chem 290:9660-73
Han, Daehee; Walsh, Matthew C; Kim, Kwang Soon et al. (2015) Microbiota-independent ameliorative effects of antibiotics on spontaneous th2-associated pathology of the small intestine. PLoS One 10:e0118795
Lin, Jingjing; Lee, Daekee; Choi, Yongwon et al. (2015) The scaffold protein RACK1 mediates the RANKL-dependent activation of p38 MAPK in osteoclast precursors. Sci Signal 8:ra54
Ko, Ryeojin; Park, Jin Hee; Ha, Hyunil et al. (2015) Glycogen synthase kinase 3? ubiquitination by TRAF6 regulates TLR3-mediated pro-inflammatory cytokine production. Nat Commun 6:6765
Lee, Jang Eun; Walsh, Matthew C; Hoehn, Kyle L et al. (2015) Acetyl CoA Carboxylase 2 Is Dispensable for CD8+ T Cell Responses. PLoS One 10:e0137776
Walsh, Matthew C; Lee, JangEun; Choi, Yongwon (2015) Tumor necrosis factor receptor- associated factor 6 (TRAF6) regulation of development, function, and homeostasis of the immune system. Immunol Rev 266:72-92
Lee, JangEun; Walsh, Matthew C; Hoehn, Kyle L et al. (2014) Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J Immunol 192:3190-9

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