Functional restoration of exhausted CD4(+) and CD8(+) T cells in chronic viral infection by vinegar-processed flos of Daphne genkwa.
T-cell exhaustion has become an important issue in chronic infection because exhausted antigen-specific T cells show impaired abilities to eradicate persistently infected pathogens and produce effector cytokines, such as IFN-γ and TNF-α. Thus, strategies to either restore endogenous exhausted T cell responses or provide functional T cells are needed for therapeutics of chronic infection. Despite promising developments using antibodies and cell immunotherapy, there have been no reported attempts to restore exhausted T cells using treatment with materials derived from natural resources. Here, using a mouse model of chronic infection with lymphocytic choriomeningitis virus (LCMV), we found that vinegar-processed flowers (flos) of Daphne genkwa (vp-genkwa), which was composed mainly of four index components, restored exhausted CD4(+) and CD8(+) T cells significantly, as corroborated by evidence that vp-genkwa treatment enhanced functional LCMV-specific CD4(+) and CD8(+) T cells, both quantitatively and qualitatively. Furthermore, pretreatment with vp-genkwa prevented the generation of exhausted LCMV-specific CD8(+) T cells. Such restorations of exhausted LCMV-specific CD4(+) and CD8(+) T cells by vp-genkwa were closely associated with reduced viral burden in sera and tissues. More interestingly, vp-genkwa treatment induced down-regulation of negative molecules, such as PD-1 and Tim-3, in exhausted CD4(+) and CD8(+) T cells with more apparent down-regulation of Tim-3, suggesting that Tim-3 molecule may be a major target in restoring exhausted T cell responses. Collectively, these results provide valuable new insights into the use of vp-genkwa to develop a therapeutic strategy for chronic human diseases, such as hepatitis B and C virus, human immunodeficiency virus, and cancers.
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea.
Erdenebileg
E
Uyangaa
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea.
Jin Young
JY
Choi
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea.
Ajit Mahadev
AM
Patil
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea.
Jin Hyoung
JH
Kim
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea.
Seong Bum
SB
Kim
Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 626-870, Republic of Korea.
Koanhoi
K
Kim
Natural Medicine Research Center, KRIBB, 30-Yeongudanji-ro, Ochang-eup, Cheongwon-gun, ChungBuk 363-883, Republic of Korea.
Hyung Won
HW
Ryu
Natural Medicine Research Center, KRIBB, 30-Yeongudanji-ro, Ochang-eup, Cheongwon-gun, ChungBuk 363-883, Republic of Korea.
Sei-Ryang
SR
Oh
College of Veterinary Medicine and Bio-Safety Research Institute, Chonbuk National University, Jeonju 561-756, Republic of Korea; Department of Bioactive Materials Sciences, Graduate School, Chonbuk National University, Jeonju 561-756, Republic of Korea. Electronic address: vetvirus@chonbuk.ac.kr.
Seong Kug
SK
Eo
D019342:Acetic Acid; D000818:Animals; D001117:Arenaviridae Infections / Q000276:immunology* / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease / Q000188:drug therapy / Q000517:prevention & control; D032364:Daphne; D004195:Disease Models, Animal; D015536:Down-Regulation; D035264:Flowers; D000072597:Hepatitis A Virus Cellular Receptor 2; D008217:Lymphocytic choriomeningitis virus; D051379:Mice; D008810:Mice, Inbred C57BL; D008517:Phytotherapy; D028321:Plant Preparations / Q000627:therapeutic use*; D011991:Receptors, Virus / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D019562:Viral Load / Q000187:drug effects*
C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D028321:Plant Preparations; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha; D019342:Acetic Acid
Chronic viral infection; Daphne genkwa; Exhausted T cells; Tim-3 molecule; Vinegar-processed flos